3-aminocyclopentanecarboxamides as modulators of chemokine receptors

ABSTRACT

The present invention is directed to compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     which are modulators of chemokine receptors. The compounds of the invention, and compositions thereof, are useful in the treatment of diseases related to chemokine receptor expression and/or activity.

CROSS-REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 60/752,320 filed Dec. 21, 2005 and U.S. ProvisionalPatent Application Ser. No. 60/752,477 filed Dec. 21, 2005, all of whichare incorporated by reference herein in their entireties.

FIELD OF THE INVENTION

The present invention relates to compounds that modulate the activity ofchemokine receptors such as CCR2 and CCR5. In some embodiments, thecompounds modulate both CCR2 and CCR5. The compounds can be used, forexample, to treat diseases associated with chemokine receptor expressionor activity.

BACKGROUND OF THE INVENTION

The migration and transport of leukocytes from blood vessels intodiseased tissues is involved in the initiation of normaldisease-fighting inflammatory responses. The process, also known asleukocyte recruitment, is also related to the onset and progression oflife-threatening inflammatory, as well as debilitating autoimmunediseases. The resulting pathology of these diseases derives from theattack of the body's immune system defenses on normal tissues.Accordingly, preventing and blocking leukocyte recruitment to targettissues in inflammatory, autoimmune disease and cancer would be a highlyeffective approach to therapeutic intervention.

The different classes of leukocyte cells that are involved in cellularimmune responses include monocytes, lymphocytes, neutrophils,eosinophils and basophils. In most cases, lymphocytes are the leukocyteclass that initiates, coordinates, and maintains chronic inflammatoryresponses, and blockage of these cells from entering inflammatory sitesis desirable. Lymphocytes attract monocytes to the tissue sites, which,collectively with lymphocytes, are responsible for most of the actualtissue damage that occurs in inflammatory disease. Infiltration of thelymphocytes and/or monocytes is known to lead to a wide range ofchronic, autoimmune diseases, and also organ transplant rejection. Thesediseases include, but are not limited to, rheumatoid arthritis, chroniccontact dermatitis, inflammatory bowel disease, lupus, systemic lupuserythematosus, multiple sclerosis, atherosclerosis, psoriasis,sarcoidosis, idiopathic pulmonary fibrosis, dermatomyositis, skinpemphigoid and related diseases, (e.g., Pemphigus vulgaris, P.foliacious, P. elythematosis), glomerulonephritides, vasculitides,hepatitis, diabetes, allograft rejection, and graft-versus-host disease.

The process by which leukocytes leave the bloodstream, accumulate atinflammatory sites, and start disease is believed to have at least threesteps which have been described as (1) rolling, (2) activation/firmadhesion and (3) transendothelial migration [Springer, T. A., Nature346:425-433 (1990); Lawrence and Springer, Cell 65:859-873 (1991);Butcher, E. C., Cell 67:1033-1036 (1991)]. The second step is mediatedat the molecular level by chemoattractant receptors. Chemoattractantreceptors on the surface of leukocytes then bind chemoattractantchemokines which are secreted by cells at the site of damage orinfection. Receptor binding activates leukocytes, increases theadhesiveness of the adhesion molecules that mediate transendothelialmigration, and promotes directed migration of the cells toward thesource of the chemoattractant chemokine.

Chemotactic chemokines (leukocyte chemoattractant/activating factors)also known as chemokines, also known as intercrines and SIS chemokines,are a group of inflammatory/immunomodulatory polypeptide factors ofmolecular weight 6-15 kDa that are released by a wide variety of cellssuch as macrophages, monocytes, eosinophils, neutrophils, fibroblasts,vascular endotherial cells, smooth muscle cells, and mast cells, atinflammatory sites (reviewed in Luster, New Eng. J Med., 338, 436-445(1998) and Rollins, Blood, 90, 909-928 (1997)). Also, chemokines havebeen described in Oppenheim, J. J. et al., Annu. Rev. Immunol.,9:617-648 (1991); Schall and Bacon, Curr. Opin. Immunol., 6:865-873(1994); Baggiolini, M., et al., and Adv. Immunol., 55:97-179 (1994).Chemokines have the ability to stimulate directed cell migration, aprocess known as chemotaxis. Each chemokine contains four cysteineresidues (C) and two internal disulfide bonds. Chemokines can be groupedinto two subfamilies, based on whether the two amino terminal cysteineresidues are immediately adjacent (CC family) or separated by one aminoacid (CXC family). These differences correlate with the organization ofthe two subfamilies into separate gene clusters. Within each genecluster, the chemokines typically show sequence similarities between 25to 60%. The CXC chemokines, such as interleukin-8 (IL-8),neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatoryactivity protein (MGSA) are chemotactic primarily for neutrophils and Tlymphocytes, whereas the CC chemokines, such as RANTES, MIP-13, themonocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5)and the eotaxins (-1 and -2) are chemotactic for, among other celltypes, macrophages, T lymphocytes, eosinophils, dendritic cells, andbasophils. There also exist the chemokines lymphotactin-1,lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine)that do not fall into either of the major chemokine subfamilies.

MCP-1 (also known as MCAF (abbreviation for macrophage chemotactic andactivating factor) or JE) is a CC chemokine produced bymonocytes/macrophages, smooth muscle cells, fibroblasts, and vascularendothelial cells and causes cell migration and cell adhesion ofmonocytes (see for example Valente, A. J., et al., Biochemistry, 1988,27, 4162; Matsushima, K., et al., J. Exp. Med., 1989, 169, 1485;Yoshimura, T., et al., J. Immunol., 1989, 142, 1956; Rollins, B. J., etal., Proc. Natl. Acad. Sci. USA, 1988, 85, 3738; Rollins, B. J., et al.,Blood, 1991, 78, 1112; Jiang, Y., et al., J. Immunol., 1992, 148, 2423;Vaddi, K., et al., J. Immunol., 1994, 153, 4721), memory T lymphocytes(see for example Carr, M. W., et al., Proc. Natl. Acad. Sci. USA, 1994,91, 3652), T lymphocytes (see for example Loetscher, P., et al., FASEBJ., 1994, 8, 1055) and natural killer cells (see for example Loetscher,P., at al., J. Immunol., 1996, 156, 322; Allavena, P., at al., Eur. J.Immunol., 1994, 24, 3233), as well as mediating histamine release bybasophils (see for example Alam, R., et al., J. Clin. Invest., 1992, 89,723; Bischoff, S. C., et al., J. Exp. Med., 1992, 175, 1271; Kuna, P.,et al., J. Exp. Med., 1992, 175, 489). In addition, high expression ofMCP-1 has been reported in diseases where accumulation ofmonocyte/macrophage and/or T cells is thought to be important in theinitiation or progression of diseases, such as atherosclerosis (see forexample Hayes, I. M., et al., Arterioscler. Thromb. Vasc. Biol., 1998,18, 397; Takeya, M. et al., Hum. Pathol., 1993, 24, 534; Yla-Herttuala,S., et al., Proc. Natl. Acad. Sol. USA, 1991, 88, 5252; Nelken, N. A.,J. Clin. Invest., 1991, 88, 1121), rheumatoid arthritis (see for exampleKoch, A. E., et al., J. Clin. Invest., 1992, 90, 772; Akahoshi, T., etal., Arthritis Rheum., 1993, 36, 762; Robinson, E., et al., Clin. Exp.Immunol., 101, 398), nephritis (see for example Noris, M., et al., Lab.Invest., 1995, 73, 804; Wada, T., at al., Kidney Int., 1996, 49, 761;Gesualdo, L., et al., Kidney Int., 1997, 51, 155), nephropathy (see forexample Saitoh, A., et al., J. Clin. Lab. Anal., 1998, 12, 1; Yokoyama,H., et al., J. Leukoc. Biol., 1998, 63, 493), pulmonary fibrosis,pulmonary sarcoidosis (see for example Sugiyama, Y., et al., InternalMedicine, 1997, 36, 856), asthma (see for example Karina, M., et al., J.Invest. Allergol. Olin. Immunol., 1997, 7, 254; Stephene, T. H., Am. J.Respir. Crit. Care Med., 1997, 156, 1377; Sousa, A. R., et al., Am. J.Respir. Cell Mol. Biol., 1994, 10, 142), multiple sclerosis (see forexample McManus, C., et al., J. Neuroimmunol., 1998, 86, 20), psoriasis(see for example Gillitzer, R., et al., J. Invest. Dermatol., 1993, 101,127), inflammatory bowel disease (see for example Grimm, M. C., et al.,J. Leukoc. Biol., 1996, 59, 804; Reinecker, H. C., et al.,Gastroenterology, 1995, 106, 40), myocarditis (see for example Seino,Y., et al., Chemokine, 1995, 7, 301), endometriosis (see for exampleJolicoeur, C., et al., Am. J. Pathol., 1998, 152, 125), intraperitonealadhesion (see for example Zeyneloglu, H. B., et al., Human Reproduction,1998, 13, 1194), congestive heart failure (see for example Aurust, P.,et al., Circulation, 1998, 97, 1136), chronic liver disease (see forexample Marra, F., et al., Am. J. Pathol., 1998, 152, 423), viralmeningitis (see for example Lahrtz, F., et al., Eur. J. Immunol., 1997,27, 2484), Kawasaki disease (see for example Wong, M.; et al., J.Rheumatol., 1997, 24, 1179) and sepsis (see for example Salkowski, C.A.; et al., Infect. Immun., 1998, 66, 3569). Furthermore, anti-MCP-1antibody has been reported to show an inhibitory effect or a therapeuticeffect in animal models of rheumatoid arthritis (see for exampleSchimmer, R. C., et al., J. Immunol., 1998, 160, 1466; Schrier, D. J.,J. Leukoc. Biol., 1998, 63, 359; Ogata, H., et al., J. Pathol., 1997,182, 106), multiple sclerosis (see for example Karpus, W. J., et al., J.Leukoc. Biol., 1997, 62, 681), nephritis (see for example Lloyd, C. M.,et al., J. Exp. Med., 1997, 185, 1371; Wada, T., et al., FASEB J., 1996,10, 1418), asthma (see for example Gonzalo, J.-A., et al., J. Exp. Med.,1998, 188, 157; Lukacs, N. W., J. Immunol., 1997, 158, 4398),atherosclerosis (see for example Guzman, L. A., et al., Circulation,1993, 88 (suppl.), 1-371), delayed type hypersensitivity (see forexample Rand, M. L., et al., Am. J. Pathol., 1996, 148, 855), pulmonaryhypertension (see for example Kimura, H., et al., Lab. Invest., 1998,78, 571), and intraperitoneal adhesion (see for example Zeyneloglu, H.B., et al., Am. J. Obstet. Gynecol., 1998, 179, 438). A peptideantagonist of MCP-1, MCP-1(9-76), has been also reported to inhibitarthritis in the mouse model (see Gong, J.-H., J. Exp., 4ed., 1997, 186,131), as well as studies in MCP-1-deficient mice have shown that MCP-1is essential for monocyte recruitment in vivo (see Lu, B., et al., J.Exp. Med., 1998, 187, 601; Gu, L., et al., Moll. Cell, 1998, 2, 275).

Chronic obstructive pulmonary disease (COPD) ranks among the most commoncauses of death in Western societies. It is defined by a progressivedecline in lung function, only partly reversible by bronchodilatordrugs. COPD is characterized by chronic inflammation in the airways oralveoli that differs from that seen in asthma, involving increasednumbers of neutrophils, macrophages, CD8+ T cells, and/or mast cells inthe airway walls, alveolar compartments, and vascular smooth muscle.Cytokines associated with COPD are believed to include tumor necrosisfactor (TNF)-alpha, interferon (IFN)-gamma, interleukin (IL)-1 beta,IL-6, IL-8 and MCP-1. CCR2 is known to be a receptor for MCP-1, andrecent data support a role for MCP-1 and CCR2 in airway remodeling andinflammation directly or via macrophages. Thus, antagonists of CCR2 arean attractive approach to therapeutic treatment of COPD (De Boer, W. I.,Chest, 2002, 121, 209S-218S).

The literature indicates that chemokines such as MCP-1 and MIP-1αattract monocytes and lymphocytes to disease sites and mediate theiractivation and thus are thought to be intimately involved in theinitiation, progression and maintenance of diseases deeply involvingmonocytes and lymphocytes, such as atherosclerosis, restenosis,rheumatoid arthritis, psoriasis, asthma, ulcerative colitis, nephritis(nephropathy), multiple sclerosis, pulmonary fibrosis, myocarditis,hepatitis, pancreatitis, sarcoidosis, Crohn's disease, endometriosis,congestive heart failure, viral meningitis, cerebral infarction,neuropathy, Kawasaki disease, and sepsis (see for example Rovin, B. H.,et al., Am. J. Kidney. Dis., 1998, 31, 1065; Lloyd, C., et al., Curr.Opin. Nephrol. Hypertens., 1998, 7, 281; Conti, P., et al., Allergy andAsthma Proc., 1998, 19, 121; Ransohoff, R. M., et al., Trends Neurosci.,1998, 21, 154; MacDermott, R. P., et al., Inflammatory Bowel Diseases,1998, 4, 54).

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal through theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration.

Genes encoding receptors of specific chemokines have been cloned, and itis known that these receptors are G protein-coupled seven-transmembranereceptors present on various leukocyte populations. So far, at leastfive CXC chemokine receptors (CXCR1-CXCR5) and eight CC chemokinereceptors (CCR1-CCR10) have been identified. For example IL-8 is aligand for CXCR1 and CXCR2, MIP-1α is a ligand for CCR1 and CCR5, andMCP-1 is a ligand for CCR2A and CCR2B (for reference, see for example,Holmes, W. E., et al., Science 1991, 253, 1278-1280; Murphy P. M., etal., Science, 253, 1280-1283; Neote, K. et al, Cell, 1993, 72, 415-425;Charo, I. F., et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 2752-2756;Yamagami, S., et al., Biochem. Biophys. Res. Commun., 1994, 202,1156-1162; Combadier, C., et al., The Journal of Biological Chemistry,1995, 270, 16491-16494, Power, C. A., et al., J. Biol. Chem., 1995, 270,19495-19500; Samson, M., et al., Biochemistry, 1996, 35, 3362-3367;Murphy, P. M., Annual Review of Immunology, 1994, 12, 592-633). It hasbeen reported that lung inflammation and granuroma formation aresuppressed in CCR1-deficient mice (see Gao, J.-L., et al., J. Exp. Med.,1997, 185, 1959; Gerard, C., et al., J. Clin. Invest., 1997, 100, 2022),and that recruitment of macrophages and formation of atheroscleroticlesion decreased in CCR2-deficient mice (see Boring, L., et al., Nature,1998, 394, 894; Kuziel, W. A., et al., Proc. Natl. Acad. Sci., USA,1997, 94, 12053; Kurihara, T., et al., J. Exp. Med., 1997, 186, 1757;Boring, L., et al., J. Clin. Invest., 1997, 100, 2552).

Chemokine receptors are also known as coreceptors for viral entryleading to viral infection such as, for example, HIV infection. Reversetranscription and protein processing are the classic steps of the virallife cycle which antiretroviral therapeutic agents are designed toblock. Although many new drugs that are believed to block viral entryhold promise, there is currently no agent to which HIV-1 has not beenable to acquire resistance. Multiple rounds of viral replication arerequired to generate the genetic diversity that forms the basis ofresistance. Combination therapy in which replication is maximallysuppressed remains a cornerstone of treatment with entry inhibitors, aswith other agents. The targeting of multiple steps within the viralentry process is believed to have the potential for synergy(Starr-Spires et al., Clin. Lab. Med., 2002, 22(3), 681).

HIV-1 entry into CD4(+) cells requires the sequential interactions ofthe viral envelope glycoproteins with CD4 and a coreceptor such as thechemokine receptors CCR5 and CXCR4. A plausible approach to blockingthis process is to use small molecule antagonists of coreceptorfunction. The TAK-779 molecule is one such antagonist of CCR5 that actsto prevent HIV-1 infection. TAK-779 inhibits HIV-1 replication at themembrane fusion stage by blocking the interaction of the viral surfaceglycoprotein gp120 with CCR5. The binding site for TAK-779 on CCR5 islocated near the extracellular surface of the receptor, within a cavityformed between transmembrane helices 1, 2, 3, and 7 (Dragic et al.,Proc. Natl. Acad. Sci. USA, 2000, 97(10), 5639).

The chemokine receptors CXCR4 and CCR5 are believed to be used asco-receptors by the T cell-tropic (X4) and macrophage-tropic (R5) HIV-1strains, respectively, for entering their host cells. Propagation of R5strains of HIV-1 on CD4 lymphocytes and macrophages requires expressionof the CCR5 coreceptor on the cell surface. Individuals lacking CCR5(CCR5 Delta 32 homozygous genotype) are phenotypically normal andresistant to infection with HIV-1. Viral entry can be inhibited by thenatural ligands for CXCR4 (the CXC chemokine SDF-1) and CCR5 (the CCchemokines RANTES, MIP-1alpha and MIP-1 beta). The first non-peptidiccompound that interacts with CCR5, and not with CXCR4, is a quaternaryammonium derivative, called TAK-779, which also has potent but variableanti-HIV activity (De Clercq et al., Antivir. Chem. Chemother. 2001, 12Suppl. 1, 19.

SCH-C (SCH 351125) is another small molecule inhibitor of HIV-1 entryvia the CCR5 coreceptor. SCH-C, an oxime-piperidine compound, is aspecific CCR5 antagonist as determined in multiple receptor binding andsignal transduction assays. This compound specifically inhibits HIV-1infection mediated by CCR5 in U-87 astroglioma cells but has no effecton infection of CXCR4-expressing cells. (Strizki et al, Proc. Natl.Acad. Sci. USA, 2001, 98(22), 12718 or Tremblay et al., AntimicrobialAgents and Chemotherapy, 2002, 46(5), 1336).

AD101, chemically related to SCH-C, also inhibits the entry of humanimmunodeficiency virus type 1 (HIV-1) via human CCR5. It has been foundthat AD101 inhibits HIV-1 entry via rhesus macaque CCR5 while SCH-C doesnot. Among the eight residues that differ between the human and macaqueversions of the coreceptor, only one, methionine-198, accounts for theinsensitivity of macaque CCR5 to inhibition by SCH-C. Position 198 is inCCR5 transmembrane (TM) helix 5 and is not located within the previouslydefined binding site for AD101 and SCH-C, which involves residues in TMhelices 1, 2, 3, and 7. Based on studies of amino acid substitutions inCCR5, it has been suggested that the region of CCR5 near residue 198 caninfluence the conformational state of this receptor. (Bill ick et al.,2004, J. Virol., 78(8), 4134).

The identification of compounds that modulate the activity of chemokinereceptors represents a desirable drug design approach for the neededdevelopment of pharmacological agents for the treatment of diseasesassociated with chemokine receptor activity. The compounds of thepresent invention help fulfill these and other needs.

SUMMARY OF THE INVENTION

The present invention provides compounds of Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, whereinconstituent members are provided herein.

The present invention further provides compositions comprising acompound of Formula I and a pharmaceutically acceptable carrier.

The present invention further provides methods of modulating activity ofa chemokine receptor comprising contacting the chemokine receptor with acompound of Formula I.

The present invention further provides methods of treating a diseaseassociated with expression or activity of a chemokine receptor in apatient comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula I.

The present invention further provides methods of treating HIV infectionin a patient comprising administering to said patient a therapeuticallyeffective amount of a compound of Formula I.

The present invention further provides a compound of the invention foruse in therapy.

The present invention further provides a compound of the invention forthe preparation of a medicament for use in therapy.

DETAILED DESCRIPTION Compounds

The present invention provides, inter alfa, compounds of Formula I:

or pharmaceutically acceptable salts or prodrugs thereof, wherein:

a dashed line indicates an optional bond;

W is:

V is N, NO or CR⁵;

X is N, NO or CR²;

Y is N, NO or CR³;

Z is N, NO or CR⁴; wherein no more than one of V, X, Y and Z is NO;

L is C₁₋₄ alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, C(O), C(O)NR⁹,S(O), S(O)NR⁹, S(O)₂, or S(O)₂NR⁹;

R^(A), R^(A1), R^(B) and R^(BI) are each, independently, H, OH, halo,C₁₋₆alkyl, C₁₋₆ alkenyl, C₁₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆haloalkoxy, heterocyclyl, carbocyclyl, NR¹⁰R¹², NR¹⁰CO₂R¹¹;NR¹⁰CONR¹⁰R¹², NR¹⁰SO₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, CN, CONR¹⁰R¹², CO₂R¹⁰, NO₂,SR¹⁰, SOR¹⁰, SO₂R¹⁰, or SO₂—NR¹⁰R¹²;

R¹ is C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₀₋₆alkyl)-O—(C₁₋₆ alkyl), —(C₀₋₆alkyl)-S—(C₁₋₆ alkyl),—(C₀₋₆alkyl)-(C₃₋₇cycloalkyl)-(C₀₋₆ alkyl), OH, OR¹⁰, SR₁₀, COR¹¹,CO₂R¹⁰, CONR¹⁰R¹², carbocyclyl, heterocyclyl, CN, NR¹⁰R¹², NR¹⁰SO₂R¹⁰,NR¹⁰COR¹⁰, NR¹⁰CO₂R¹⁰, NR¹⁰CONR¹², CR¹⁰R¹¹CO₂R¹⁰ or CR¹⁰R¹¹OCOR¹⁰;

R², R³, R⁴, R⁵ and R⁶ are each, independently, H, OH, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, C₁₋₆ thioalkoxy, NR¹⁰R¹²,NR¹⁰CO₂R¹¹, NR¹⁰CONR¹⁰R¹², NR¹⁰SO₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, heterocyclyl,carbocyclyl, carbocyclyloxy, heterocyclyloxy, CN, NO₂, COR¹¹, CONR¹⁰R¹²,CO₂R¹⁰, NO₂, SR¹⁰, SOR¹⁰, SO₂R¹⁰; or SO₂—NR¹⁰R¹²;

R⁷ is H or C₁₋₈ alkyl optionally substituted by 1, 2, 3, 4, 5 or 6substituents independently selected from halo, C₁₋₁₀ haloalkyl, Cy, CN,NO₂, OR^(a), C(O)R^(b), C(O)NR^(c)R^(d), C(O)OR^(a), OC(O)R^(b),OC(O)NR^(c)R^(d), NR^(c)R^(d), NR^(c)C(O)R^(b), NR^(c)C(O)NR^(c)R^(d),NR^(c)C(O)OR^(a), S(O)R^(b), S(O)NR^(c)R^(d), S(O)₂R^(b),NR^(c)S(O)₂R^(b), and S(O)₂NR^(c)R^(d);

or R⁷ is H, C₁₋₆alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, halo, —O—C₁₋₆alkyl, CN,—NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)SO₂R^(14a), —COR^(11a),—CONR^(12a)R^(12a), phenyl and heterocycle, where the alkyl, phenyl, andheterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy, —CO₂H,—CO₂—C₁₋₆alkyl, and trifluoromethyl, and —SO₂C₁₋₆alkyl which isunsubstituted or substituted with 1-6 substituents selected from:hydroxy, halo, —O—C₁₋₆alkyl, CN, —NR^(12a)R^(12a), —NR^(12a)COR^(13a),—NR^(12a)SO₂R^(14a), —COR^(11a), —CONR^(12a)R^(12a), phenyl andheterocycle, where the alkyl, phenyl, and heterocycle are unsubstitutedor substituted with 1-3 substituents selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃ alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, and trifluoromethyl;

or R⁷ is H, unsubstituted or substituted with 1-3 substituents selectedfrom: halo, hydroxy, —CO₂H, —CO₂C₁₋₆alkyl, and —O—C₁₋₃alkyl;

R⁸ is C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, aryl,cycloalkyl, heteroaryl, or heterocycloalkyl, wherein said C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl,heteroaryl, or heterocycloalkyl is optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from oxo, hydroxy, halo,C₁₋₄ alkyl, C₁₋₄alkoxy, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′, —(C₁₋₄alkyl)-Cy′, —C(O)—R^(a), CN,NO₂, —(CH₂)_(q)—OR^(a′), —(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)R^(b′),—(CH₂)_(q)—C(O)NR^(c′)R^(d′), —(CH₂)_(q)—C(O)OR^(a′),—(CH₂)_(q)—OC(O)R^(b′), —(CH₂)_(q)—OC(O)NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)C(O)R^(b′),—(CH₂)_(q)—NR^(c′)C(O)NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)C(O)OR^(a′),—(CH₂)_(q)—S(O)R^(b′), —(CH₂)_(q)—S(O)NR^(c′)R^(d′),—(CH₂)_(q)—S(O)₂R^(b′), —(CH₂)_(q)—NR^(c′)S(O)₂R^(b′), and—(CH₂)_(q)—S(O)₂NR^(b′)R^(d′);

or R⁸ is selected from C₁₋₁₀alkyl, —SO₂C₁₋₁₀alkyl, pyridyl or phenyl,unsubstituted or substituted with 1-5 substituents selected from:hydroxy, halo, —O—C₁₋₁₀alkyl, CN, —NR^(12a)R^(12a), —NR^(12a)COR^(13a),—NR^(12a)SO₂R^(14a), —COR^(11a), —CONR^(12a)R^(12a), —SO₂R^(14a),heterocycle, ═O (where the oxygen is connected via a double bond),phenoxy and phenyl, where the alkyl, phenyl, phenoxy and heterocycle areunsubstituted or substituted with 1-3 substituents selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —COR^(11a), —CN, —NR^(12a)R^(12a),—SO₂R^(14a), —NR^(12a)COR^(13a), —NR^(12a)SO₂R^(14a), and—CONR^(12a)R^(12a), where the alkyl and alkoxy are optionallysubstituted with 1-5 fluoro; or R⁸ is a group of formula

Y and Z are independently selected from —O—, —NR^(12b), —S—, —SO—, SO₂—,—CR^(12b)R^(12b)—, —NSO₂R^(14b)—, —NCOR^(13b)—, —CR^(12b)COR^(11b)—,—CR^(12b)OCOR^(13b)—, —C— and —CO—;

R^(8a) and R^(8a′) are independently selected from: hydrogen, C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and —COR^(11b), fluoro, —O—C₁₋₃alkyl unsubstitutedor substituted with 1-3 fluoro, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl,hydroxy, —COR^(11b), —OCOR^(13b);

or R⁷ and R^(8a) together are C₂₋₄alkyl or C₀₋₂alkyl-O—C₁₋₃alkyl,forming a 5-7 membered ring;

R^(9a) and R^(9a′) are independently selected from: hydrogen, C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₆alkoxy, hydroxy and —COR^(11b), COR^(11b), hydroxy and —O—C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,hydroxy and —COR^(11b);

or R^(8a) and R^(9a) together are C₁₋₄alkyl or C₀₋₃alkyl-O—C₀₋₃alkyl,forming a 3-6 membered ring;

R^(10a) is selected from: hydrogen, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 fluoro, fluoro, —O—C₃₋₆cycloalkyl and —O—C₁₋₃alkylunsubstituted or substituted with 1-6 fluoro;

or R^(8a) and R^(10a) together are C₂₋₃alkyl, forming a 5-6 memberedring, where said alkyl is unsubstituted or substituted with 1-3substituents independently selected from halo, hydroxy, —COR^(11b),C₁₋₃alkyl and C₁₋₃alkoxy;

or R^(8a) and R^(10a) together are O—C₁₋₂alkyl-O—C₁₋₂alkyl, forming a6-8 membered ring, where said alkyl is unsubstituted or substituted with1-3 substituents independently selected from halo, hydroxy, —COR^(11b),C₁₋₃alkyl and C₁₋₃alkoxy;

or R^(8a) and R^(10a) together are —O—C₁₋₂alkyl-O—, forming a 6-7membered ring, where said alkyl is unsubstituted or substituted with 1-3substituents independently selected from halo, hydroxy, —COR^(11b),C₁₋₃alkyl and C₁₋₃alkoxy;

R^(11a) and R^(11b) are independently selected from: hydroxy, hydrogen,C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl, phenyl and C₃₋₆cycloalkyl, where saidalkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl;

R^(12a) and R^(12b) are independently selected from: hydrogen,C₁₋₆alkyl, benzyl, phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl,benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3substituents independently selected from: halo, hydroxy, C₁₋₃alkyl,C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, and trifluoromethyl; also R^(12a) andR^(12b) can be selected from: C₁₋₆alkyl unsubstituted or substitutedwith 1-6 substituents selected from fluoro, C₁₋₃alkoxy, hydroxy and—COR^(11b), fluoro, —O—C₁₋₃alkyl unsubstituted or substituted with 1-6fluoro, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, hydroxy, —O—C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and —COR^(11b);

R^(13a) and R^(13b) are independently selected from: hydrogen,C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl, phenyl, C₃₋₆ cycloalkyl, where thealkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl;

R^(14a) and R^(14b) are independently selected from: hydroxy, C₁₋₆alkyl,—O—C₁₋₆alkyl, benzyl, phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl,benzyl, and cycloalkyl groups are unsubstituted or substituted with 1-3substituents independently selected from: halo, hydroxy, C₁₋₃alkyl,C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, and trifluoromethyl;

Cy and Cy′ are, independently, aryl, heteroaryl, cycloalkyl, orheterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, haloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″),C(O)NR^(c″)R^(d″), C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(c″)R^(d″),NR^(c″)R^(d″), NR^(c″)C(O)R^(b″), NR^(c″)C(O)OR^(a″), S(O)R^(b″),S(O)NR^(c″)R^(d″), S(O)₂R^(b″), and S(O)₂NR^(c″)R^(d″);

R⁹ is H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl,wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynylis optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R¹⁰ is H, C₁₋₆ alkyl, benzyl, phenyl, or C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, benzyl, phenyl, or C₃₋₆ cycloalkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, OH, C₁₋₃alkyl, C₁₋₆haloalkyl, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, CO₂H, and CO₂—(O₁₋₆alkyl);

R¹¹ is H, OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, benzyl, phenyl, benzyloxy,phenyloxy, C₃₋₆cycloalkyl or C₃₋₆ cycloalkyloxy, wherein said C₁₋₆alkyl, C₁₋₆ alkoxy, benzyl, phenyl, benzyloxy, phenyloxy, C₃₋₆cycloalkyl or C₃₋₆ cycloalkyloxy, is optionally substituted with 1, 2 or3 substituents independently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃alkoxy, CO₂H, CO₂—(C₁₋₆alkyl) and CF₃;

R¹² is H, C₁₋₆ alkyl, benzyl, phenyl, or C₃₋₆ cycloalkyl, wherein saidC₁₋₆ alkyl, benzyl, phenyl, or C₃₋₆ cycloalkyl is optionally substitutedwith 1, 2, or 3 substituents independently selected from halo, OH, C₁₋₃alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl);

R^(a), R^(a′) and R^(a″) are, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆alkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(b), R^(b′) and R^(b″) are, independently, H, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(c) and R^(d) are, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl,wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl is optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R^(c) and R^(d) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(c′) and R^(d′) are, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R^(c′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

R^(c″) and R^(d″) are, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;

or R^(c″) and R^(d″) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl;

m is 0, 1, or 2;

n is 0 or 1;

p is 0 or 1; and

q is 0, 1, 2, or 3.

In some embodiments, when n is 0, R⁸ is other than a compound of theformula:

wherein Y is —O—, —S—, —NR^(12a)—, —CR^(12b)R^(12b′); R8^(a), R8^(a′),R9^(a′) and R9^(a) are independently selected from hydrogen, C₁₋₃alkoxy,C₁₋₃haloalkoxy, C₃₋₆cycloalkyloxy, hydroxy, C₁₋₆ alkyl, halo, C₃₋₆cycloalkyl, CO₂R¹⁰, OCOR¹⁰, wherein said C₁₋₆ alkyl is optionallysubstituted with one or more substituents selected from F, C₁₋₃ alkoxy,OH or CO₂R¹⁰; wherein neither R8^(a) and R8^(a′) nor R9^(a′) and R9^(a)form with the carbon atom they are attached to a 3-7 memberedspirocyclyl group.

In some embodiments, when n is 0, R⁸ is

m is 1, Y is —O—, —S—, —NR^(12b)R^(12b)—, Z is —CR^(12b)R^(12b)—,R^(12b) is hydrogen, R^(8a), R^(8a′), R^(9a′) and R^(9a) are other thanhydrogen, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₆cycloalkyloxy, hydroxy, C₁₋₆alkyl, halo, C₃₋₆ cycloalkyl, CO₂R¹⁰, OCOR¹⁰, wherein said C₁₋₆ alkyl isoptionally substituted with one or more substituents selected from F,C₁₋₃ alkoxy, OH or CO₂R¹⁰; wherein neither R^(8a) and R^(8a′) norR^(9a′) and R^(9a) form with the carbon atom they are attached to becomea 3-7 membered spirocyclyl group.

In some embodiments, when n is 0, R⁸ is

Y is —O—, —S—, —NR^(12b)—, —CR^(12b)R^(12b)—, wherein R^(8a), R^(8a′),R^(9a′) and R^(9a) are other than hydrogen, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, C₃₋₆ cycloalkyloxy, hydroxy, C₁₋₆ alkyl, halo, C₃₋₆cycloalkyl, CO₂R¹⁰ OCOR¹⁰, wherein said C₁₋₆ alkyl is optionallysubstituted with one or more substituents selected from F, C₁₋₃ alkoxy,OH or CO₂R¹⁰ wherein neither R8^(a) and R8^(a′) nor R9^(a′) and R9^(a)form with the carbon atom they are attached to become a 3-7 memberedspirocyclyl group.

In some embodiments, R⁸ is

Y is —O—, —S—, —NR^(12b)—, —CR^(12b)R^(12b)—, wherein R8^(a), and R9^(a)are other than hydrogen, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₆cycloalkyloxy, hydroxy, C₁₋₆ alkyl, halo, C₃₋₆ cycloalkyl, CO₂R¹⁰,OCOR¹⁰, wherein said C₁₋₆ alkyl is optionally substituted with one ormore substituents selected from F, C₁₋₃ alkoxy, OH or CO₂R¹⁰. Inaddition, R8^(a) and R9^(a) do not form with the carbon atom they areattached to become a 3-7 membered spirocyclyl group with the carbonatom.

In some embodiments, when n is 0, R⁸ is other than atetrahydropyran-4-yl of the formula:

wherein R8^(a), R8^(a′), R9^(a) and R9^(a′) are independently selectedfrom hydrogen, C₁₋₃ alkoxy, C₁₋₃ haloalkoxy, C₃₋₆ cycloalkyloxy,hydroxy, C₁₋₆ alkyl, halo, C₃₋₆ cycloalkyl, CO₂R¹⁰, OCOR¹⁰, wherein saidC₁₋₆ alkyl is optionally substituted with one or more substituentsselected from F, C₁₋₃ alkoxy, OH or CO₂R¹⁰; wherein neither R8^(a) andR8^(a′) nor R9^(a) and R9^(a′) form with the carbon atom they areattached to a 3-7 membered spirocyclyl group.

In some embodiments, when n is 0, R⁸ is other than atetrahydropyran-4-yl of the formula:

wherein R8^(a) and R9^(a) are independently selected from hydrogen, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, C₃₋₆ cycloalkyloxy, hydroxy, C₁₋₆alkyl, halo,C₃₋₆ cycloalkyl, CO₂R¹⁰, OCOR¹⁰, wherein said C₁₋₆ alkyl is optionallysubstituted with one or more substituents selected from F, C₁₋₃ alkoxy,OH or CO₂R¹⁰. In addition, R8^(a) and R9^(a) do not form with the carbonatom they are attached to become a 3-7 membered spirocyclyl group withthe carbon atom.

In some embodiments, when n is 0, R⁸ is other than substituted orunsubstituted tetrahydropyran-4-yl.

In some embodiments, R⁸ is other than substituted or unsubstitutedtetrahydrothiopyran-4-yl.

In some embodiments, R⁸ is other than substituted or unsubstituted4-piperidinyl.

In some embodiments, R⁸ is other than substituted or unsubstituted4-cyclohexanyl.

In some embodiments, R⁸ is

In some embodiments, R⁸ is

In some embodiments, m is 0.

In some embodiments, m is 1.

In some embodiments, m is 2.

In some embodiments, R¹² is H, C₁₋₆ alkyl, benzyl, phenyl, or C₃₋₆cycloalkyl, wherein said C₁₋₆alkyl, benzyl, phenyl, or C₃₋₆ cycloalkylis optionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, CO₂H, and CO₂—(C₁₋₆ alkyl).

In some embodiments, W is

In some embodiments, W is

In some embodiments, V is CR^(S).

In some embodiments, X is CR².

In some embodiments, Y is CR³.

In some embodiments, Z is CR⁴.

In some embodiments, X is CR²; Y is CR³; and Z is CR⁴.

In some embodiments, V is CR^(S), X is CR²; Y is CR³; and Z is CR⁴.

In some embodiments, R^(A), R^(A1), R^(B) and R^(B1) are each,independently, H, OH, halo, C₁₋₆ alkyl, C₁₋₆ alkenyl, C₁₋₆ alkynyl, C₁₋₆haloalkyl, C₁₋₆alkoxy or C₁₋₆haloalkoxy.

In some embodiments, R^(A), R^(A1), R^(B) and R^(B1) are each,independently, H, OH or C₁₋₆ alkoxy.

In some embodiments, R^(A), R^(A1), R^(B) and R^(B1) are each,independently, H or OH.

In some embodiments, R¹ is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, —(C₀₋₆alkyl)-O—(C₁₋₆ alkyl), or heterocyclyl.

In some embodiments, R¹ is C₁₋₆ alkyl.

In some embodiments, R¹ is prop-2-yl.

In some embodiments, one of R⁵ and R⁶ is other than H.

In some embodiments, one of R⁵ and R⁶ is C₁₋₄ haloalkyl.

In some embodiments, R⁶ is C₁₋₄ haloalkyl.

In some embodiments, R⁶ is CF₃.

In some embodiments, R⁷ is H.

In some embodiments, R⁷ is C₁₋₈ alkyl.

In some embodiments, R⁸ is C₁₋₁₀ alkyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl, each optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl,C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′,—(C₁₋₄ alkyl)-Cy′, CN, NO₂, —(CH₂)_(q)—OR^(a′), —(CH₂)_(q)—SR^(a′),—(CH₂)_(q)—C(O)R^(b′), —(CH₂)_(q)—C(O)NR^(c′)R^(d′),—(CH₂)_(q)—C(O)OR^(a′), —(CH₂)_(q)—OC(O)R^(b′),—(CH₂)_(q)—OC(O)NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)R^(b′), —(CH₂)_(q)—NR^(c′)C(O)NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)OR^(a′), —(CH₂)_(q)—S(O)R^(b′),—(CH₂)_(q)—S(O)NR^(c′)R^(d′), —(CH₂)_(q)—S(O)₂R^(b′),—(CH₂)_(q)—NR^(c′)S(O)₂R^(b′), and —(CH₂)_(q)—S(O)₂NR^(c′)R^(d′).

In some embodiments, R⁸ is C₁₋₁₀ alkyl optionally substituted with 1, 2,3, 4, 5, or 6 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl,cyanoalkyl, Cy′, —(C₁₋₄ alkyl)-Cy′, CN, NO₂, —(CH₂)_(q)—OR^(a′),—(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)R^(b′), —(CH₂)_(q)—C(O)NR^(c′)R^(d′),—(CH₂)_(q)—C(O)OR^(a′), —(CH₂)_(q)—OC(O)R^(b′),—(CH₂)_(q)—OC(O)NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)R^(b′), —(CH₂)_(q)—NR^(c′)C(O)NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)OR^(a′), —(CH₂)_(q)—S(O)R^(b′),—(CH₂)_(q)—S(O)NR^(c′)R^(d′), —(CH₂)_(q)—S(O)₂R^(b′),—(CH₂)_(q)—NR^(c′)S(O)₂R^(b′), and —(CH₂)_(q)—S(O)₂NR^(c′)R^(d′).

In some embodiments, R⁸ is aryl or heteroaryl, each optionallysubstituted with 1, 2, 3, 4, 5, or 6 substituents independently selectedfrom halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′, —(C₁₋₄ alkyl)-Cy′, CN, NO₂,—(CH₂)_(q)—OR^(a′), —(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)R^(b′),—(CH₂)_(q)—C(O)NR^(c′)R^(d′), —(CH₂)_(q)—C(O)OR^(a′),—(CH₂)_(q)—OC(O)R^(b′), —(CH₂)_(q)—OC(O)NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)C(O)R^(b′),—(CH₂)_(q)—NR^(c′)C(O)NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)C(O)OR^(a′),—(CH₂)_(q)—S(O)R^(b′), —(CH₂)_(q)—S(O)NR^(c′)R^(d′),—(CH₂)_(q)—S(O)₂R^(b′), —(CH₂)_(q)—NR^(c′)S(O)₂R^(b′), and—(CH₂)_(q)—S(O)₂NR^(c′)R^(d′).

In some embodiments, R⁸ is cycloalkyl or heterocycloalkyl, eachoptionally substituted with 1, 2, 3, 4, 5, or 6 substituentsindependently selected from halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′, —(C₁₋₄alkyl)-Cy′, CN, NO₂, —(CH₂)_(q)—OR^(a′), —(CH₂)_(q)—SR^(a′),—(CH₂)_(q)—C(O)R^(b′), —(CH₂)_(q)—C(O)NR^(c′)R^(d′),—(CH₂)_(q)—C(O)OR^(a′), —(CH₂)_(q)—OC(O)R^(b′),—(CH₂)_(q)—OC(O)NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)R^(b′), —(CH₂)_(q)—NR^(c′)C(O)NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)OR^(a′), —(CH₂)_(q)—S(O)R^(b′),—(CH₂)_(q)—S(O)NR^(c′)R^(d′), —(CH₂)_(q)—S(O)₂R^(b′),—(CH₂)_(q)—NR^(c′)S(O)₂R^(b′), and —(CH₂)_(q)—S(O)₂NR^(c′)R^(d′).

In some embodiments, R⁸ is phenyl optionally substituted with 1, 2, 3,4, 5, or 6 substituents independently selected from halo, C₁₋₄ alkyl,C₂₋₄ alkenyl, C₂₋₄ alkynyl, C_(i) haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄cyanoalkyl, Cy′, —(C₁₋₄ alkyl)-Cy′, CN, NO₂, —(CH₂)_(q)—OR^(a′),—(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)R^(b′), —(CH₂)_(q)—C(O)NR^(c′)R^(d′),—(CH₂)_(q)—C(O)OR^(a′), —(CH₂)_(q)—OC(O)R^(b′),—(CH₂)_(q)—OC(O)NR^(c′)R^(d′), —(CH₂)_(q)—NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)R^(b′), —(CH₂)_(q)—NR^(c′)C(O)NR^(c′)R^(d′),—(CH₂)_(q)—NR^(c′)C(O)OR^(a′), —(CH₂)_(q)—S(O)R^(b′),—(CH₂)_(q)—S(O)NR^(c′)R^(d′), —(CH₂)_(q)—S(O)₂R^(b′),—(CH₂)_(q)—NR^(c′)S(O)₂R^(b′), and —(CH₂)_(q)—S(O)₂NR^(c′)R^(d′).

In some embodiments, R⁸ is selected from: C₁₋₈alkyl optionallysubstituted with hydroxyl, C₁₋₆alkyl substituted with 1-6 fluoro,C₁₋₆alkyl substituted with —COR¹¹, benzyl, unsubstituted or substitutedwith 1-3 substituents selected from: hydroxy, methoxy, chloro, fluoro,—COR¹¹, methyl and trifluoromethyl, —CH₂-pyridyl, unsubstituted orsubstituted with 1-3 substituents selected from: hydroxy, methoxy,chloro, fluoro, methyl and trifluoromethyl.

In some embodiments, R^(8a) is selected from: hydrogen, C₁₋₃alkylunsubstituted or substituted with 1-6 fluoro, —O—C₁₋₃alkyl, fluoro andhydroxyl.

In some embodiments, R^(8a) is halo.

In some embodiments, R^(8a) is F.

In some embodiments, R^(8a) is H.

In some embodiments, R^(9a) is H.

In some embodiments, R^(10a) is H.

In some embodiments, Y is O.

In some embodiments, n is 0 and R⁸ is C₁₋₈ alkyl, substituted with 1, 2,or 3 substituents independently selected from OH, halo, and—(CH₂)_(q)—C(O)R^(b′).

In some embodiments, n is 1, L is C₁₋₄ alkylenyl, and R⁸ is aryl orheteroaryl each optionally substituted with 1, 2, or 3 substituentsselected from halo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, OR^(a′), and—(CH₂)_(q)—C(O)R^(b′).

In some embodiments, L is C₁₋₄ alkylenyl.

In some embodiments, L is methylene.

In some embodiments, L is C(O) or S(O)₂.

In some embodiments, n is 0.

In some embodiments, n is 1.

In some embodiments, compounds of the invention have Formula Ia:

In some embodiments, compounds of the invention have Formula Ib, lc orId:

In some embodiments, compounds of the invention have Formula Ie or If:

In some embodiments, compounds of the invention have Formula Ig:

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. It isspecifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges. Forexample, the term “C₁₋₆ alkyl” is specifically intended to individuallydisclose methyl, ethyl, C₃ alkyl, C₄ alkyl, C₅ alkyl, and C₆ alkyl.

For compounds of the invention in which a variable appears more thanonce, each variable can be a different moiety selected from the Markushgroup defining the variable. For example, where a structure is describedhaving two R groups that are simultaneously present on the samecompound; the two R groups can represent different moieties selectedfrom the Markush group defined for R.

It is further appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, canalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, can also be provided separately orin any suitable subcombination.

As used herein, the term “alkyl” is meant to refer to a saturatedhydrocarbon group which is straight-chained or branched. Example alkylgroups include methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.,n-pentyl, isopentyl, neopentyl), and the like. An alkyl group cancontain from 1 to about 20, from 2 to about 20, from 1 to about 10, from1 to about 8, from 1 to about 6, from 1 to about 4, or from 1 to about 3carbon atoms. The term “alkylenyl” refers to a divalent alkyl linkinggroup.

As used herein, “alkenyl” refers to an alkyl group having one or moredouble carbon-carbon bonds. Example alkenyl groups include ethenyl,propenyl, cyclohexenyl, and the like. The term “alkenylenyl” refers to adivalent linking alkenyl group.

As used herein, “alkynyl” refers to an alkyl group having one or moretriple carbon-carbon bonds. Example alkynyl groups include ethynyl,propynyl, and the like. The term “alkynylenyl” refers to a divalentlinking alkynyl group.

As used herein, “haloalkyl” refers to an alkyl group having one or morehalogen substituents. Example haloalkyl groups include CF₃, C₂F₅, CHF₂,CCl₃, CHCl₂, C₂Cl₅, and the like.

As used herein, “carbocyclyl” groups are saturated (i.e., containing nodouble or triple bonds) or unsaturated (i.e., containing one or moredouble or triple bonds) cyclic hydrocarbon moieties. Carbocyclyl groupscan be mono-, poly- (e.g., 2, 3 or 4 fused rings). Example carbocyclylgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclopentenyl, 1,3-cyclopentadienyl, cyclohexenyl,norbornyl, norpinyl, norcarnyl, adamantyl, phenyl, and the like.Carbocyclyl groups can be aromatic (e.g., “aryl”) or non-aromatic (e.g.,“cycloalkyl”). In some embodiments, carbocyclyl groups can have fromabout 3 to about 30 carbon atoms, about 3 to about 20, about 3 to about10, or about 3 to about 7 ring-forming carbon atoms.

As used herein, “aryl” refers to monocyclic or polycyclic (e.g., having2, 3 or 4 fused rings) aromatic hydrocarbons such as, for example,phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and thelike. In some embodiments, aryl groups have from 6 to about 20 carbonatoms.

As used herein, “cycloalkyl” refers to non-aromatic carbocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups. Cycloalkyl groupscan include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings)ring systems as well as Spiro ring systems. Example cycloalkyl groupsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl,norbornyl, norpinyl, norcarnyl, adamantyl, and the like. Also includedin the definition of cycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thecycloalkyl ring, for example, benzo derivatives of pentane, pentene,hexane, and the like. In some embodiments, cycloalkyl groups can havefrom about 3 to about 10, about 3 to about 10, or about 3 to about 7ring-forming carbon atoms. In some embodiments, the cycloalkyl group canhave 0, 1, 2, 3, 4 or 5 double or triple bonds. In yet furtherembodiments, one or more ring-forming carbon atoms of a cycloalkyl groupcan be substituted by an oxo or sulfido group.

As used herein, “heterocyclyl” or “heterocycle” refers to a saturated orunsaturated cyclic hydrocarbon wherein one or more of the ring-formingatoms is a heteroatom such as O, S, or N. Heterocyclyl groups can bearomatic (e.g., “heteroaryl”) or non-aromatic (e.g.,“heterocycloalkyl”). Heterocyclyl groups can also correspond tohydrogenated and partially hydrogenated heteroaryl groups. Heterocyclylgroups can include mono- or polycyclic (e.g., having 2, 3 or 4 fusedrings) ring systems. Heterocyclyl groups can be characterized as having3-14 or 3-7 ring-forming atoms. In some embodiments, heterocyclyl groupscan contain, in addition to at least one heteroatom, from about 1 toabout 13, about 2 to about 10, or about 2 to about 7 carbon atoms andcan be attached through a carbon atom or heteroatom. In furtherembodiments, any ring-forming carbon or heteroatom can be oxidized(e.g., have an oxo or sulfido substituent), or a nitrogen atom can bequaternized. Examples of heterocyclyl groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like, as well asany of the groups listed below for “heteroaryl” and “heterocycloalkyl.”Further example heterocycles include pyrimidinyl, phenanthridinyl,phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl,phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,3,6-dihydropyridyl, 1,2,3,6-tetrahydropyridyl,1,2,5,6-tetrahydropyridyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thia-diazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl,xanthenyl, octahydro-isoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzo-thiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazolinyl, methylenedioxyphenyl, morpholinyl,naphthyridinyl, deca-hydroquinolinyl, 2H,6H-1,5,2dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl and isoxazolyl. Further examples of heterocycles includeazetidin-1-yl, 2,5-dihydro-1H-pyrrol-1-yl, piperindin-1yl,piperazin-1-yl, pyrrolidin-1-yl, isoquinol-2-yl, pyridin-1-yl,3,6-dihydropyridin-1-yl, 2,3-dihydroindol-1-yl,1,3,4,9-tetrahydrocarbolin-2-yl, thieno[2,3-c]pyridin-6-yl,3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indol-2-yl,1,2,4,4a,5,6-hexahydro-pyrazino[1,2-a]quinolin-3-yl,pyrazino[1,2-a]quinolin-3-yl, diazepan-1-yl,1,4,5,6-tetrahydro-2H-benzo[f]isoquinolin-3-yl,1,4,4a,5,6,10b-hexahydro-2H-benzo[f]isoquinolin-3-yl,3,3a,8,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-2-yl, and2,3,4,7-tetrahydro-1H-azepin-1-yl, azepan-1-yl.

As used herein, “heteroaryl” groups refer to an aromatic heterocyclehaving at least one heteroatom ring member such as sulfur, oxygen, ornitrogen. Heteroaryl groups include monocyclic and polycyclic (e.g.,having 2, 3 or 4 fused rings) systems. Examples of heteroaryl groupsinclude without limitation, pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl,imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, benzofuryl,benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl,tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, benzothienyl,purinyl, carbazolyl, benzimidazolyl, indolinyl, and the like. In someembodiments, the heteroaryl group has from 1 to about 20 carbon atoms,and in further embodiments from about 3 to about 20 carbon atoms. Insome embodiments, the heteroaryl group contains 3 to about 14, 3 toabout 7, or 5 to 6 ring-forming atoms. In some embodiments, theheteroaryl group has 1 to about 4, 1 to about 3, or 1 to 2 heteroatoms.

As used herein, “heterocycloalkyl” refers to non-aromatic heterocyclesincluding cyclized alkyl, alkenyl, and alkynyl groups where one or moreof the ring-forming carbon atoms is replaced by a heteroatom such as anO, N, or S atom. Example “heterocycloalkyl” groups include morpholino,thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl,2,3-dihydrobenzofuryl, 1,3-benzodioxole, benzo-1,4-dioxane, piperidinyl,pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, imidazolidinyl, and the like. Also includedin the definition of heterocycloalkyl are moieties that have one or morearomatic rings fused (i.e., having a bond in common with) to thenonaromatic heterocyclic ring, for example phthalimidyl, naphthalimidyl,and benzo derivatives of heterocycles such as indolene and isoindolenegroups. In some embodiments, the heterocycloalkyl group has from 1 toabout 20 carbon atoms, and in further embodiments from about 3 to about20 carbon atoms. In some embodiments, the heterocycloalkyl groupcontains 3 to about 14, 3 to about 7, or 5 to 6 ring-forming atoms. Insome embodiments, the heterocycloalkyl group has 1 to about 4, 1 toabout 3, or 1 to 2 heteroatoms. In some embodiments, theheterocycloalkyl group contains 0 to 3 double bonds. In someembodiments, the heterocycloalkyl group contains 0 to 2 double or triplebonds.

As used herein, “spirocyclyl” refers to a 3-14 membered cycloalkyl or3-14 membered heterocycloalkyl group sharing one atom with a furthercycloalkyl or heterocycloalkyl group to which it is attached.

As used herein, “halo” or “halogen” includes fluoro, chloro, bromo, andiodo.

As used herein, “alkoxy” refers to an —O-alkyl group. Example alkoxygroups include methoxy, ethoxy, propoxy (e.g., n-propoxy andisopropoxy), t-butoxy, and the like.

As used herein, “thioalkoxy” refers to an —S-alkyl group.

As used herein, “haloalkoxy” refers to an —O-haloalkyl group. An examplehaloalkoxy group is OCF₃.

As used herein, “carbocyclyloxy” refers to —O-carbocyclyl.

As used herein, “heterocyclyloxy” refers to —O-heterocyclyl.

As used herein, “cycloalkyloxy” refers to —O-cycloalkyl.

As used herein, “carbocyclylalkyl” refers to alkyl substituted bycarbocyclyl.

As used herein, “aralkyl” or “arylalkyl” refers to an alkyl groupsubstituted by an aryl group.

As used herein, “cycloalkylalkyl” refers to an alkyl group substitutedby an cycloalkyl group.

As used herein, “heterocyclylalkyl” refers to an alkyl moietysubstituted by a heterocarbocyclyl group. Example heterocyclylalkylgroups include “heteroarylalkyl” (alkyl substituted by heteroaryl) and“heterocycloalkylalkyl” (alkyl substituted by heterocycloalkyl). In someembodiments, heterocyclylalkyl groups have from 3 to 24 carbon atoms inaddition to at least one ring-forming heteroatom.

As used herein, “hydroxyalkyl” refers to an alkyl group substituted by ahydroxyl group.

As used herein, “cyanoalkyl” refers to an alkyl group substituted by acyano group.

As used herein, “amino” refers to NH₂.

As used herein “oxo” refers to ═O.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds describedherein, and all such stable isomers are contemplated in the presentinvention. Cis and trans geometric isomers of the compounds of thepresent invention are described and may be isolated as a mixture ofisomers or as separated isomeric forms.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method Includes fractionalrecrystallizaion using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asp-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention also include tautomeric forms, such asketo-enol tautomers.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

The present invention also includes pharmaceutically acceptable salts ofthe compounds described herein. As used herein, “pharmaceuticallyacceptable salts” refers to derivatives of the disclosed compoundswherein the parent compound is modified by converting an existing acidor base moiety to its salt form. Examples of pharmaceutically acceptablesalts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidicresidues such as carboxylic acids; and the like. The pharmaceuticallyacceptable salts of the present invention include the conventionalnon-toxic salts or the quaternary ammonium salts of the parent compoundformed, for example, from non-toxic inorganic or organic acids. Thepharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), eachof which is incorporated herein by reference in its entirety.

The present invention also includes prodrugs of the compounds describedherein. As used herein, “prodrugs” refer to any covalently bondedcarriers which release the active parent drug when administered to amammalian subject. Prodrugs can be prepared by modifying functionalgroups present in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds wherein hydroxyl, amino,sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of alcohol and amine functional groups in the compounds ofthe invention. Preparation and use of prodrugs is discussed in T.Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are hereby incorporated by referencein their entirety.

Synthesis

Compounds of the invention, including salts, hydrates, and solvatesthereof, can be prepared using known organic synthesis techniques andcan be synthesized according to any of numerous possible syntheticroutes.

The reactions for preparing compounds of the invention can be carriedout in suitable solvents which can be readily selected by one of skillin the art of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected.

Preparation of Compounds of the Invention can Involve the Protection andDeprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in T. W. Greene and P. G.M. Wuts, Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons,Inc., New York (1999), which is incorporated herein by reference in itsentirety.

Reactions can be monitored according to any suitable method known in theart. For example, product formation can be monitored by spectroscopicmeans, such as nuclear magnetic resonance spectroscopy (e.g., ¹H or ¹³C)infrared spectroscopy, spectrophotometry (e.g., UV-visible), or massspectrometry, or by chromatography such as high performance liquidchromatography (HPLC) or thin layer chromatography.

Exemplary synthetic routes to compounds of the invention are provided inSchemes 1-13 below, where constituent members of the depicted formulaeare defined herein.

3-Aminopentanecarboxylic acids of formula 1-5 can be prepared using theprotocol described in Scheme 1. The commercially available carboxylicacid 1-1 can be converted to an ester such as a methyl ester bytreatment with iodomethane/potassium carbonate in DMF. The resultingester 1-2 can be subjected to an alkylation with a halide such as aniodide (R¹I) using a base such as lithium hexamethyldisilazide (LHMDS)to provide the alkylated product 1-3 as a mixture of cis and transdiastereomers (4:1 ratio). The minor trans diastereomer can be removedby crystallization following hydrolysis of the ester to an acid. Theresulting enantiopure acid 1-4 can be subjected to a hydrogenation usinga catalyst such as Pd—C to afford the saturated carboxylic acid 1-5,

Cyclopentanecarboxylic acids of formula 2-5 can be prepared using theprocedures outlined in Scheme 2. The commercially available3-oxocyclopentanecarboxylic acid 2-1 can be converted to an ester suchas methyl ester. The ketone of the resulting ester 2-2 can be protectedby treatment with trimethyl orthoformate in the presence of an acidiccatalyst such as paratoluenesulfonic acid. Alkylation of the resultingketal 2-3 with an alkyl iodide (R¹¹) can be accomplished using a basesuch as LHM DS. Hydrolysis of the alkylated ester 2-4 using a base suchas LiOH, NaOH or KOH provides the carboxylic acids of formula 2-5.

Piperazine derivatives can be prepared using the procedures depicted inScheme 3. Coupling of a piperazine derivative of formula 3-2 with aniodobenzene derivative of formula 3-1 using copper(I) iodide andpotassium phosphate gives rise to the intermediate 3-3. Removal of theBoc group using an acid such as HCl in dioxane or TFA provides thepiperazine derivatives of formula 3-4.

Alternatively, piperazine derivatives (formula 4-3) can be prepared bydisplacement of a 2-chloropyridine or 2-chloropyrimidine derivative offormula 4-1 with a piperazine derivative of formula 4-2.

Alternatively, piperazine derivatives can be prepared using a sequenceas illustrated in Scheme 5. The commercially available3,5-dibromopyridine 5-1 can be converted to 3-bromo-5-iodopyridine 5-2by treatment with isopropylmagnesium bromide and iodine. Coupling of theresulting iodo with a piperazine derivative of formula 3-2 can beaccomplished using copper(I) iodide and potassium phosphate. Followingconversion of the bromo of the resulting intermediate 5-3 to iodo usingisopropylmagnesium bromide and iodine, the iodo can be displaced withtrifluoromethyl by treatment with Me₃SiCF₃/CuI/KF/DMF to afford thetrifluoromethylpyridine derivative of formula 5-5. Removal of the Bocusing an acid such as HCl in dioxane or TFA yields the piperazinederivatives of formula 5-6.

Piperidine or tetrahydropyridine derivatives can be synthesized as shownin Scheme 6. Lithiation of a bromo- or iodobenzene derivative of formula6-1 with an alkyllithium such as n-butyllithium or tert-butyllithiumfollowed by quenching with a ketone derivative of formula 6-2 providesthe tertiary alcohol of formula 6-3. Following dehydration using adehydrating agent such as thionyl chloride/pyridine, the resultingolefin 6-4 can be reduced by hydrogenation using a catalyst such as Pdon carbon. Treatment of 6-3, 6-4 and 6-5 with an acid such as HCl indioxane or TFA provides compounds of formulae 6-6, 6-7 and 6-8.

Alternatively, piperidine or tetrahydropyridine derivatives can besynthesized as illustrated in Scheme 7. A commercially available2-chloropyridine or 2-chloropyrilidine derivative of formula 4-1 can beconverted to 2-bromopyridine derivative of formula 7-1 by treatment withBrSiMe₃. Using similar procedures described in Scheme 6, piperidine andtetrahydropyridine derivatives of formula 7-5 and 7-6 can be obtainedfrom 7-1.

Alternatively, piperidine or tetrahydropyridine derivatives can besynthesized as outlined in Scheme 8.3-Nitro-5-trifluoromethylpyridin-2-ol can be obtained by nitration ofthe commercially available 5-trifluoromethylpyridin-2-ol (8-1).Following conversion of the hydroxy group in 8-2 to chloro, theresulting chloro compound 8-3 is subjected to a hydrogenation using acatalyst such as Pd on carbon to give 3-amino-5-trifluoromethylpyridine8-4. Diazotization of 8-4 using NaNO₂/HBr in the presence of Cu(I)Brprovides 3-bromo-5-trifluoromethylpyridine 8-5. Following the proceduresdescribed in Scheme 6, 8-5 can be converted to piperidine ortetrahydropyridine derivatives of formulae 8-9 and 8-10.

Compounds of formula 9-3 can be prepared according to Scheme 9.Lithiation of arylhalide or heteroarylhalide (ArX, X=Br, I) usingn-butyllithium followed by addition of cyclohexanedione mono-etheyleneketal (9-1) gives rise to the alcohol intermediate 9-2. Treatment of theketal 9-2 with aqueous acid yields the ketone product 9-3.

Final compounds of formula I can be assembled using the methodsdescribed in Scheme 10. A carboxylic acid of formula 1-5 can becondensed with an amine of formula 10-1 using a standard amide formationagent such as BOP or PyBrop (coupling agent). Following removal of theBoc using an acid such as HCl or TFA, the resulting amine 10-3 can besubjected to alkylation, reductive amination or acylation, etc. toprovide final compounds of formula 10-4.

Alternatively, compounds of the invention can be assembled according toScheme 11. Coupling of a carboxylic acid of formula 2-5 with an amine offormula 10-1 using a standard amide formation method can produce amidesof formula 11-1. Following conversion of the ketal to a ketone using anaqueous acid, reductive amination of the resulting ketone 11-2 with anamine using a reducing agent such as sodium triacertoxyborohydrideprovides compounds of formula 11-3.

Methods

In some embodiments, compounds of the invention can modulate activity ofone or more chemokine receptors. The term “modulate” is meant to referto an ability to increase or decrease activity of a receptor.Accordingly, compounds of the invention can be used in methods ofmodulating a chemokine receptor by contacting the receptor with any oneor more of the compounds or compositions described herein. In someembodiments, compounds of the present invention can act as inhibitors ofchemokine receptors. In further embodiments, the compounds of theinvention can be used to modulate activity of a chemokine receptor in anindividual in need of modulation of the receptor by administering amodulating amount of a compound of Formula I.

Chemokine receptors to which the present compounds bind and/or modulateinclude any chemokine receptor. In some embodiments, the chemokinereceptor belongs to the CC family of chemokine receptors including, forexample, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, and CCR10. Insome embodiments, the chemokine receptor is CCR2. In some embodiments,the chemokine receptor is CCR5. In some embodiments, the chemokinereceptor binds and/or modulates both CCR2 and CCR5.

The compounds of the invention can be selective. By “selective” is meantthat a compound binds to or inhibits a chemokine receptor with greateraffinity or potency, respectively, compared to at least one otherchemokine receptor.

Compounds of the invention can be dual inhibitors or binders of CCR2 andCCR5, meaning that the compounds of the invention can bind to or inhibitboth CCR2 and CCR5 with greater affinity or potency, respectively, thanfor other chemokine receptors such as CCR1, CCR3, CCR4, CCR6, CCR7,CCR8, and CCR10. In some embodiments, the compounds of the inventionhave binding or inhibition selectivity for CCR2 and CCR5 over any otherchemokine receptor. Selectivity can be at least about 10-fold, at leastabout 20-fold, at least about 50-fold, at least about 100-fold, at leastabout 200-fold, at least about 500-fold or at least about 1000-fold.Binding affinity and inhibitor potency can be measured according toroutine methods in the art, such as according to the assays providedherein.

The present invention further provides methods of treating a chemokinereceptor-associated disease or disorder in an individual (e.g., patient)by administering to the individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention or a pharmaceutical composition thereof. A chemokinereceptor-associated disease can Include any disease, disorder orcondition that is directly or indirectly linked to expression oractivity of the chemokine receptor. A chemokine receptor-associateddisease can also include any disease, disorder or condition that can beprevented, ameliorated, or cured by modulating chemokine receptoractivity. A chemokine receptor-associated disease can further includeany disease, disorder or condition that is characterized by binding ofan infectious agent such as a virus or viral protein with a chemokinereceptor. In some embodiments, the chemokine receptor-associated diseaseis a CCR5-associated disease such as HIV infection.

Example chemokine receptor-associated diseases, disorders and conditionsinclude inflammation and inflammatory diseases, pain, pain associatedwith osteoarthritis, pain associated with rheumatoid arthritis,neuropathic pain, cardiovascular diseases, obesity, immune disorders,cancer, liver firbosis, and viral infections. Example inflammatorydiseases include diseases having an inflammatory component such asasthma, seasonal and perennial allergic rhinitis, sinusitis,conjunctivitis, age-related macular degeneration, food allergy,scombroid poisoning, psoriasis, urticaria, pruritus, eczema,inflammatory bowel disease, thrombotic disease, otitis media, livercirrhosis, cardiac disease, Alzheimer's disease, sepsis, restenosis,atherosclerosis, multiple sclerosis, Crohn's disease, ulcerativecolitis, hypersensitivity lung diseases, drug-induced pulmonaryfibrosis, chronic obstructive pulmonary disease (COPD), rheumatoidarthritis, and nephritis, ulcerative colitis, atopic dermatitis, stroke,acute nerve injury, sarcoidosis, hepatitis, endometriosis, neuropathicpain, hypersensitivity pneumonitis, eosinophilic pneumonias,delayed-type hypersensitivity, interstitial lung disease (ILD) (e.g.,idiopathic pulmonary fibrosis, or ILD associated with rheumatoidarthritis, systemic lupus erythematosus, ankylosing spondylitis,systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis), eye disorders (e.g., retinal neurodegeneration,choroidal neovascularization, etc.) and the like. Example immunedisorders include rheumatoid arthritis, psoriatic arthritis, systemiclupus erythematosus, myastenia gravis, juvenile onset diabetes;glomerulonephritis, autoimmune throiditis, organ transplant rejectionincluding allograft rejection and graft-versus-host disease. Examplecancers include cancers such as breast cancer, ovarian cancer, multiplemyeloma and the like that are characterized by infiltration ofmacrophages (e.g., tumor associated macrophages, TAMs) into tumors ordiseased tissues. Example viral infections include Herpes infection,influenza, HIV infection or AIDS.

Further diseases treatable by administration of a compound of thepresent invention include, for example, autoimmune nephritis, lupusnephritis, Goodpasture's syndrome nephritis and Wegeners granulomatosisnephritis, lupus erythematosus, Goodpasture's syndrome and Wegenersgranulomatosis.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” the chemokine receptor with a compound of theinvention includes the administration of a compound of the presentinvention to an individual or patient, such as a human, having achemokine receptor, as well as, for example, introducing a compound ofthe invention into a sample containing a cellular or purifiedpreparation containing the chemokine receptor.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing:

(1) preventing the disease; for example, preventing a disease, conditionor disorder in an individual who may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease (non-limiting examples arepreventing hypersensitivity lung diseases, drug-induced pulmonaryfibrosis, chronic obstructive pulmonary disease (COPD),graft-versus-host disease and/or allograft rejection aftertransplantation, or preventing allergic reactions such as atopicdermatitis, or seasonal or perennial allergic rhinitis);

(2) inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual who is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology)such as inhibiting the autoimmune response in hypersensitivity lungdiseases, drug-induced pulmonary fibrosis, chronic obstructive pulmonarydisease (COPD), rheumatoid arthritis, lupus or psoriasis, or inhibitingtumor growth or stabilizing viral load in the case of a viral infection;and

(3) ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing the pathology and/or symptomatology) such as decreasingthe autoimmune response in hypersensitivity lung diseases, drug-inducedpulmonary fibrosis, chronic obstructive pulmonary disease (COPD),rheumatoid arthritis, lupus or psoriasis, or shrinking a tumorassociated with cancer or lowering viral load in the case of a viralinfection.

One or more additional pharmaceutical agents such as, for example,antibodies, anti-inflammatory agents, immunosuppressants, andchemotherapeutics can be used in combination with the compounds of thepresent invention for treatment of chemokine receptor-associateddiseases, disorders or conditions. The agents can be combined with thepresent compounds in a single dosage form, or the agents can beadministered simultaneously or sequentially as separate dosage forms.

One or more additional pharmaceutical agents such as, for example,anti-viral agents, antibodies, anti-inflammatory agents, insulinsecretagogues and sensitizers, serum lipid and lipid-carrier modulatingagents, and/or immunosuppressants can be used in combination with thecompounds of the present invention for treatment of chemokinereceptor-associated diseases, disorders or conditions. The agents can becombined with the present compounds in a single or continuous dosageform, or the agents can be administered simultaneously or sequentiallyas separate dosage forms.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present invention can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors and otherantiviral drugs.

Suitable antiviral agents contemplated for use in combination with thecompounds of the present invention can comprise nucleoside andnucleotide reverse transcriptase inhibitors (NRTIs), non-nucleosidereverse transcriptase inhibitors (NNRTIs), protease inhibitors, entryinhibitors, fusion inhibitors, maturation inhibitors, and otherantiviral drugs.

Example suitable NRTIs include zidovudine (AZT); didanosine (ddI);zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir(1592U89); adefovir dipivoxil [bis(POM)-PMEA]; lobucavir (BMS-180194);BCH-10652; emitricitabine [(−)-FTC]; beta-L-FD4 (also called beta-L-D4Cand named beta-L-2′,3′-dicleoxy-5-fluoro-cytidene); DAPD,((−)-beta-D-2,6,-diamino-purine dioxolane); and lodenosine (FddA).

Typical suitable NNRTIs include nevirapine (BI-RG-587); delaviradine(BHAP, U-90152); efavirenz (DMP-266); PNU-142721; AG-1549; MKC-442(1-(ethoxy-methyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione); and (+)-calanolide A (NSC-675451) and B.

Typical suitable protease inhibitors include saquinavir (Ro 31-8959);ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir(141W94); lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; andAG-1 549.

Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12,pentafuside, enfuvirtide, C-34, the cyclotriazadisulfonamide CADA,PA-457 and Yissum Project No. 11607.

In some embodiments, anti-inflammatory or analgesic agents contemplatedfor use in combination with the compounds of the present invention cancomprise, for example, an opiate agonist, a lipoxygenase inhibitor suchas an inhibitor of 5-lipoxygenase, a cyclooxygenase inhibitor such as acyclooxygenase-2 inhibitor, an interleukin inhibitor such as aninterleukin-1 inhibitor, a TNF inhibitor such as infliximab, etanercept,or adalimumab an NNMA antagonist, an inhibitor of nitric oxide or aninhibitor of the synthesis of nitric oxide, a non-steroidalantiinflammatory agent, or a cytokine-suppressing antiinflammatoryagent, for example, such as acetaminophen, aspirin, codeine, fentanyl,ibuprofen, indomethacin, ketodolac, morphine, naproxen, phenacetin,piroxicam, a steroidal analgesic, sufentanyl, sunlindac, tenidap, andthe like. Similarly, the instant compounds can be administered with apain reliever; a potentiator such as caffeine, an H2-antagonist,simethicone, aluminum or magnesium hydroxide; a decongestant such asphenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline,ephinephrine, naphazoline, xylometazoline, propylhexedfine, orlevo-desoxyephedrine; an anffitussive such as codeine, hydrocodone,caramiphen, carbetapentane, or dextramethorphan; a diuretic; and asedating or non-sedating antihistamine.

In some embodiments, pharmaceutical agents contemplated for use incombination with the compounds of the present invention can comprise butare not limited to (a) VLA-4 antagonists such as those described in U.S.Pat. No. 5,510,332, WO95/15973, WO96/01644, WO96/06108, WO96/20216,WO96/229661, WO96/31206, WO96/4078, WO97/030941, WO97/022897 WO98/426567 WO98/53814, WO98/53817, WO98/538185, WO98/54207, andWO98/58902; (b) steroids such as beclornethasone, methylpi-ednisolone,betarnethasone, prednisone, dexamethasone, and hydrocortisone; (c)immunosuppressants such as cyclosporin, tacrolimus, rapamycin and otherFK506 type immunosuppressants; (d) antihistamines (HI-histamineantagonists) such as bromopheniramine, chlorpheniramine,dexchlorpheniramine, triprolidine, clemastine, diphenhydramine,diphenylpyraline, tripelennamine, hydroxyzine, methdilazine,promethazine, trimeprazine, azatadine, cyproheptadine, antazoline,pheniramine pyrilamine, asternizole, terfenadine, loratadine,cetirizine, fexofenadine, desearboethoxyloratadine, and the like; (e)non-steroidal anti-asthmatics such as terbutaline, metaproterenol,fenoterol, isoethaiine, albuterol, bitolterol, pirbuterol, theophylline,cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists(e.g., zafirlukast, montelukast, pranlukast, iralukast, pobilukast,SKB-106,203), leukotriene biosynthesis inhibitors (e.g., zileuton,BAY-1005); (f) nonsteroidal antiinflammatory agents (NSAIDs) such aspropionic acid derivatives (e.g., alminoprofen, benoxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (e.g., indomethacin, acernetacin, alclofenac,clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac,ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin,and zomepirac), fenarnic acid derivatives (flufenarnic acid,meclofenamic acid, rnefenamic acid, niflumic acid and tolfenarnic acid),biphenylearboxylic acid derivatives (diflunisal and flufenisal),oxicarns (isoxicarn, piroxicam, sudoxicam and tenoxican), salicylates(acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (i) other antagonists of thechemokine receptors, especially CXCR-4, CCR1, CCR2, CCR3 and CCR5; (j)cholesterol lowering agents such as HMG-CoA reductase inhibitors(lovastatin, sirrivastatin and pravastatin, fluvastatin, atorvastatin,and other statins), sequestrants (cholestyramine and colestipol),nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrat,fenofibrate and benzafibrate), and probucol; (k) anti-inflammatorybiologic agents such as anti-TNF therapies, anti-IL-1 receptor,CTLA-4Ig, anti-CD20, and anti-VLA4 antibodies; (l) anti-diabetic agentssuch as insulin, sulfonylureas, biguanides (metformin), U.-glucosidaseinhibitors (acarbose) and orlitazones (troglitazone and pioglitazone);(m) preparations of interferon beta (interferon beta-lo., interferonbeta-1 P); (n) other compounds such as aminosalicylic acids,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thecompound of the present invention to the second active ingredient may bevaried and will depend upon the effective dose of each ingredient.

For example, a CCR2 and/or CCR5 antagonist can be used in combinationwith an anti-inflammatory pharmaceutical agent in the treatment ofinflammation, metabolic disease, autoimmune disease, cancer or viralinfection to improve the treatment response as compared to the responseto the therapeutic agent alone, without exacerbation of its toxiceffects. Additive or synergistic effects are desirable outcomes ofcombining a CCR2 and/or CCR5 antagonist of the present invention with anadditional agent. Furthermore, resistance of cancer cells to agents suchas dexamethasone can be reversible upon treatment with a CCR2 and/orCCR5 antagonist of the present invention.

Pharmaceutical Formulations and Dosage Forms

When employed as pharmaceuticals, the compounds of Formula I can beadministered in the form of pharmaceutical compositions. Thesecompositions can be prepared in a manner well known in thepharmaceutical art, and can be administered by a variety of routesdepending upon whether local or systemic treatment is desired and uponthe area to be treated. Administration can be topical (includingophthalmic and to mucous membranes including intranasal, vaginal andrectal delivery), pulmonary (e.g., by inhalation or insufflation ofpowders or aerosols, including by nebulizer; intratracheal, intranasal,epidermal and transdermal), oral or parenteral. Parenteraladministration includes intravenous, intraarterial, subcutaneous,intraperitoneal intramuscular or injection or infusion; or intracranial,e.g., intrathecal or intraventricular, administration. Parenteraladministration can be in the form of a single bolus dose, or can be, forexample, by a continuous perfusion pump. Pharmaceutical compositions andformulations for topical administration can include transdermal patches,ointments, lotions, creams, gels, drops, suppositories, sprays, liquidsand powders. Conventional pharmaceutical carriers, aqueous, powder oroily bases, thickeners and the like may be necessary or desirable.Coated condoms, gloves and the like may also be useful.

This invention also includes pharmaceutical compositions which contain,as the active ingredient, one or more of the compounds of Formula Iabove in combination with one or more pharmaceutically acceptablecarriers. In making the compositions of the invention, the activeingredient is typically mixed with an excipient, diluted by an excipientor enclosed within such a carrier in the form of, for example, acapsule, sachet, paper, or other container. When the excipient serves asa diluent, it can be a solid, semi-solid, or liquid material, which actsas a vehicle, carrier or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosols (as a solid or in a liquid medium), ointments containing, forexample, up to 10% by weight of the active compound, soft and hardgelatin capsules, suppositories, sterile injectable solutions, andsterile packaged powders.

In preparing a formulation, the active compound can be milled to providethe appropriate particle size prior to combining with the otheringredients. If the active compound is substantially insoluble, it canbe milled to a particle size of less than 200 mesh. If the activecompound is substantially water soluble, the particle size can beadjusted by milling to provide a substantially uniform distribution inthe formulation, e.g. about 40 mesh.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. Theformulations can additionally include: lubricating agents such as talc,magnesium stearate, and mineral oil; wetting agents; emulsifying andsuspending agents; preserving agents such as methyl- andpropylhydroxy-benzoates; sweetening agents; and flavoring agents. Thecompositions of the invention can be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.

The compositions can be formulated in a unit dosage form, each dosagecontaining from about 5 to about 1000 mg (1 g), more usually about 100to about 500 mg, of the active ingredient. The term “unit dosage forms”refers to physically discrete units suitable as unitary dosages forhuman subjects and other mammals, each unit containing a predeterminedquantity of active material calculated to produce the desiredtherapeutic effect, in association with a suitable pharmaceuticalexcipient.

In some embodiments, the compounds or compositions of the inventioncontain from about 5 to about 50 mg of the active ingredient. One havingordinary skill in the art will appreciate that this embodies compoundsor compositions containing from about 5 to about 10, from about 10 toabout 15, from about 15 to about 20, from about 20 to about 25, fromabout 25 to about 30, from about 30 to about 35, from about 35 to about40, from about 40 to about 45, or from about 45 to about 50 mg of theactive ingredient.

In some embodiments, the compounds or compositions of the inventioncontain from about 50 to about 500 mg of the active ingredient. Onehaving ordinary skill in the art will appreciate that this embodiescompounds or compositions containing from about 50 to about 75, fromabout 75 to about 100, from about 100 to about 125, from about 125 toabout 150, from about 150 to about 175, from about 175 to about 200,from about 200 to about 225, from about 225 to about 250, from about 250to about 275, from about 275 to about 300, from about 300 to about 325,from about 325 to about 350, from about 350 to about 375, from about 375to about 400, from about 400 to about 425, from about 425 to about 450,from about 450 to about 475, or from about 475 to about 500 mg of theactive ingredient.

In some embodiments, the compounds or compositions of the inventioncontain from about 500 to about 1000 mg of the active ingredient. Onehaving ordinary skill in the art will appreciate that this embodiescompounds or compositions containing from about 500 to about 550, fromabout 550 to about 600, from about 600 to about 650, from about 650 toabout 700, from about 700 to about 750, from about 750 to about 800,from about 800 to about 850, from about 850 to about 900, from about 900to about 950, or from about 950 to about 1000 mg of the activeingredient.

The active compound can be effective over a wide dosage range and isgenerally administered in a pharmaceutically effective amount. It willbe understood, however, that the amount of the compound actuallyadministered will usually be determined by a physician, according to therelevant circumstances, including the condition to be treated, thechosen route of administration, the actual compound administered, theage, weight, and response of the individual patient, the severity of thepatient's symptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, the active Ingredient istypically dispersed evenly throughout the composition so that thecomposition can be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulation isthen subdivided into unit dosage forms of the type described abovecontaining from, for example, 0.1 to about 1000 mg of the activeingredient of the present invention.

The tablets or pills of the present invention can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permit theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of materials can be used for such enteric layers orcoatings, such materials including a number of polymeric acids andmixtures of polymeric acids with such materials as shellac, cetylalcohol, and cellulose acetate.

The liquid forms in which the compounds and compositions of the presentinvention can be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavored syrups, aqueous or oilsuspensions, and flavored emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil, or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. In some embodiments, the compositions are administered by theoral or nasal respiratory route for local or systemic effect.Compositions in can be nebulized by use of inert gases. Nebulizedsolutions may be breathed directly from the nebulizing device or thenebulizing device can be attached to a face masks tent, or intermittentpositive pressure breathing machine. Solution, suspension, or powdercompositions can be administered orally or nasally from devices whichdeliver the formulation in an appropriate manner.

The amount of compound or composition administered to a patient willvary depending upon what is being administered, the purpose of theadministration, such as prophylaxis or therapy, the state of thepatient, the manner of administration, and the like. In therapeuticapplications, compositions can be administered to a patient alreadysuffering from a disease in an amount sufficient to cure or at leastpartially arrest the symptoms of the disease and its complications.Effective doses will depend on the disease condition being treated aswell as by the judgment of the attending clinician depending uponfactors such as the severity of the disease, the age, weight and generalcondition of the patient, and the like.

The compositions administered to a patient can be in the form ofpharmaceutical compositions described above. These compositions can besterilized by conventional sterilization techniques, or may be sterilefiltered. Aqueous solutions can be packaged for use as is, orlyophilized, the lyophilized preparation being combined with a sterileaqueous carrier prior to administration. The pH of the compoundpreparations typically will be between 3 and 11, more preferably from 5to 9 and most preferably from 7 to 8. It will be understood that use ofcertain of the foregoing excipients, carriers, or stabilizers willresult in the formation of pharmaceutical salts.

The therapeutic dosage of the compounds of the present invention canvary according to, for example, the particular use for which thetreatment is made, the manner of administration of the compound, thehealth and condition of the patient, and the judgment of the prescribingphysician. The proportion or concentration of a compound of theinvention in a pharmaceutical composition can vary depending upon anumber of factors including dosage, chemical characteristics (e.g.,hydrophobicity), and the route of administration. For example, thecompounds of the invention can be provided in an aqueous physiologicalbuffer solution containing about 0.1 to about 10% w/v of the compoundfor parenteral administration. Some typical dose ranges are from about 1μg/kg to about 1 g/kg of body weight per day. In some embodiments, thedose range is from about 0.01 mg/kg to about 100 mg/kg of body weightper day. The dosage is likely to depend on such variables as the typeand extent of progression of the disease or disorder, the overall healthstatus of the particular patient, the relative biological efficacy ofthe compound selected, formulation of the excipient, and its route ofadministration. Effective doses can be extrapolated from dose-responsecurves derived from in vitro or animal model test systems.

The compounds of the invention can also be formulated in combinationwith one or more additional active ingredients which can include anypharmaceutical agent such as antibodies, immune suppressants,anti-inflammatory agents, chemotherapeutics, lipid lowering agents, HDLelevating agents, insulin secretagogues or sensitizers, drugs used forthe treatment of rheumatoid arthritis and the like.

Rheumatoid Arthritis (RA) Treatment Regimen

Rheumatoid arthritis (RA) patients, treated aggressively with diseasemodifying agents (methotrexate, antimalarials, gold, penicillamine,sulfasalazine, dapsone, leflunamide, or biologicals), can achievevarying degrees of disease control, including complete remissions. Theseclinical responses are associated with improvement in standardizedscores of disease activity, specifically the ACR criteria whichincludes: pain, function, number of tender joints, number of swollenjoints, patient global assessment, physician global assessment,laboratory measures of inflammation (CRP and ESR), and radiologicassessment of joint structural damage. Current disease-modifying drugs(DMARDs) require continued administration to maintain optimal benefit.Chronic dosing of these agents is associated with significant toxicityand host defense compromise. Additionally, patients often becomerefractory to a particular therapy and require an alternative regimen.For these reasons, a novel, effective therapy which allows withdrawal ofstandard DMARDs would be a clinically important advance.

Patients with significant response to anti-TNF therapies (infliximab,etanercept, adalimumab), anti-IL-1 therapy (kinaret) or other diseasemodifying anti-rheumatic drugs (DMARDs) including but not limited tomethotrexate, cyclosporine, gold salts, antimalarials, penicillamine orleflunamide, who have achieved clinical remission of disease can betreated with a substance that inhibits expression and/or activity ofCCR2 including, for example, nucleic acids (e.g., antisense or siRNAmolecules), proteins (e.g., anti-CCR2 antibodies), small moleculeinhibitors (e.g., the compounds disclosed herein and other chemokinereceptor inhibitors known in the art).

In some embodiments, the substance that inhibits expression and/oractivity of CCR2 is a small molecule CCR2 inhibitor (or antagonist). TheCCR2 antagonist can be dosed orally q.d. or b.i.d at a dose not toexceed about 500 mgs a day. The patients can be withdrawn from or have adecrease in the dosage of their current therapy and would be maintainedon treatment with the CCR2 antagonist. Treating patients with acombination of CCR2 antagonist and their current therapy can be carriedout for, for example, about one to about two days, before discontinuingor dose reducing the DMARD and continuing on CCR2 antagonist.

Advantages of substituting traditional DMARDS with CCR2 antagonists arenumerous. Traditional DMARDs have serious cumulative dose-limiting sideeffects, the most common being damage to the liver, as well asimmunosuppressive actions. CCR2 antagonism is expected to have animproved long-term safety profile and will not have similarimmunosuppressive liabilities associated with traditional DMARDs.Additionally, the half-life of the biologicals is typically days orweeks, which is an issue when dealing with adverse reactions. Thehalf-life of an orally bioavailable CCR2 antagonist is expected to be onthe order of hours so the risk of continued exposure to the drug afteran adverse event is very minimal as compared to biological agents. Also,the current biologic agents (infliximab, etanercept, adalimumab,kinaret) are typically given either i.v. or s.c., requiring doctor'sadministration or patient self-injection. This leads to the possibilityof infusion reaction or injection site reactions. These are avoidableusing an orally administered CCR2 antagonist.

Diabetes and Insulin Resistance Treatment Regimen

Type 2 diabetes is one of the leading causes of morbidity and mortalityin western societies. In the vast majority of patients, the disease ischaracterized by pancreatic beta-cell dysfunction accompanied by insulinresistance in the liver and in peripheral tissues. Based on the primarymechanisms that are associated with disease, two general classes of oraltherapies are available to treat type 2 diabetes: insulin secretagogues(sulfonylureas such as glyburide) and insulin sensitizers (metformin andthiazolidinediones such as rosiglitazone). Combination therapy thataddresses both mechanisms has been shown to manage the metabolic defectsof this disease and in many instances can be shown to ameliorate theneed for exogenous insulin administration. However, with time, insulinresistance often progresses, leading to the need for further insulinsupplementation. In addition, a prediabetic state, referred to as themetabolic syndrome, has been demonstrated to be characterized byimpaired glucose tolerance, particularly in association with obesity.The majority of patients who develop type 2 diabetes begin by developinginsulin resistance, with the hyperglycemia occurring when these patientscan no longer sustain the degree of hyperinsulinemia necessary toprevent loss of glucose homeostasis. The onset of the insulin resistancecomponent is highly predictive of disease onset and is associated withan increase in the risk of developing type 2 diabetes, hypertension andcoronary heart disease.

One of the strongest correlates of impaired glucose tolerance and of theprogression from an insulin resistant state to type 2 diabetes is thepresence of central obesity. Most patients with type 2 diabetes areobese and obesity itself is associated with insulin resistance. It isclear that central adiposity is a major risk factor for the developmentof insulin resistance leading to type 2 diabetes, suggesting thatsignals from visceral fat contribute to the development of insulinresistant and progression to disease. In addition to the secretedprotein factors, obesity induces a cellular inflammatory response inwhich bone-marrow derived macrophages accumulate in adipose depots,becoming adipose tissue macrophages. Adipose tissue macrophagesaccumulate in adipose tissue in proportion to measures of adiposity.Tissue infiltrating macrophages are a source of many of the inflammatorycytokines that have been demonstrated to induce insulin resistance inadipocytes.

Adipose tissue produces MCP-1 in proportion to adiposity, suggestingthat its activity by signaling through CCR2 also might play an importantrole in the accumulation of macrophages in adipose tissue. It is unknownwhether the MCP-1/CCR2 interaction is directly responsible for monocyterecruitment to adipose tissue, whether reduced recruitment ofmacrophages to adipose tissue in humans will directly lead to thereduced production of proinflammatory molecules and whether theproinflammatory molecule production is directly linked to insulinresistance.

Patients who demonstrate insulin resistance, either prediabetic(normoglycemic) or diabetic (hyperglycemic), could be treated with asubstance that inhibits the expression and/or activity of CCR2including, for example, nucleic acids (e.g., antisense or siRNAmolecules), proteins (e.g., anti-CCR2 antibodies), small moleculeinhibitors (e.g., the compounds disclosed herein and other chemokinereceptor inhibitors known in the art). In some embodiments, thesubstance that inhibits expression and/or activity of CCR2 is a smallmolecule CCR2 inhibitor (or antagonist). The CCR2 antagonist can bedosed orally q.d. or b.i.d at a dose not to exceed about 500 mgs a day.The patients can be withdrawn from or have a decrease in the dosage oftheir current therapy and would be maintained on treatment with the CCR2antagonist. Alternately CCR2 antagonist treatment may be used tosupplement their current therapy to enhance its effectiveness or toprevent progression to further insulin dependence.

Advantages of substituting or supplementing traditional agents with CCR2antagonists are numerous. Such agents may be useful, for example, topreclude progression from a prediabetic, insulin resistant state to adiabetic state. Such agents may reduce or replace the need for the useof insulin sensitizers, with their attendant toxicities. Such agents mayalso reduce the need for, or prolong the period until, exogenous insulinsupplementation is required.

Atherosclerosis Treatment Regimen

Atherosclerosis is a condition characterized by the deposition of fattysubstances in arterial walls. Plaque encompasses such deposits of fattysubstances, cholesterol, cellular waste products, calcium and othersubstances that build up in the inner lining of an artery. Plaques cangrow large enough to significantly reduce the blood's flow through anartery. However, more significant damage occurs when the plaque becomesunstable and ruptures. Plaques that rupture cause blood clots to formthat can block blood flow or break off and travel to other parts of thebody. If the clot blocks a blood vessel that feeds the heart, it causesa heart attack. If it blocks a blood vessel that feeds the brain, itcauses a stroke. Atherosclerosis is a slow, complex disease thattypically starts in childhood and often progresses as people grow older.

A high level of cholesterol in the blood is a major risk factor forcoronary heart disease. Based on cholesterol as a primary composition ofplaque, the advance of plaque formation has been managed by thereduction of circulating cholesterol or by elevation ofcholesterol-carrying high density lipoproteins (HDL). Circulatingcholesterol can be reduced, for example, by inhibiting its synthesis inthe liver using or by reducing update from food. Such medicaments thatact through these mechanism may include medicines that are used to lowerhigh cholesterol levels: bile acid absorbers, lipoprotein synthesisinhibitors, cholesterol synthesis inhibitors and fibric acidderivatives. Circulating HDL can additionally be elevated byadministration of, for example, probuchol or high doses of niacin.Therapy that addresses multiple mechanisms has been shown to slowdisease progression and progression to plaque rupture.

Atherosclerosis is typically accompanied by a cellular inflammatoryresponse in which bone-marrow derived macrophages accumulate in fattystreaks along the vessel wall, becoming foam cells. Foam cells are asource of many of the inflammatory cytokines that have been demonstratedto induce plaque progression and of the enzymes that can promote plaquedestabilization. Atherosclerotic tissue also produces MCP-1, suggestingthat its activity by signaling through CCR2 also might play an importantrole in the accumulation of macrophages as foam cells in plaques.CCR2−/− mice have been demonstrated to have significantly reducedmacrophages in fatty streaks generated as a result of high fat diet orgenetic alteration in lipid metabolism.

Patients who demonstrate high circulating cholesterol, low HDL, orelevated circulating CRP or present with vessel wall plaque by imaging,or any other evidence of the presence of atherosclerosis could betreated with a substance that inhibits the expression and/or activity ofCCR2 including, for example, nucleic acids (e.g., antisense or siRNAmolecules), proteins (e.g., anti-CCR2 antibodies), small moleculeinhibitors (e.g., the compounds disclosed herein and other chemokinereceptor inhibitors known in the art). In some embodiments, thesubstance that inhibits expression and/or activity of CCR2 is a smallmolecule CCR2 inhibitor (or antagonist) such as a compound of theinvention. The CCR2 antagonist can be dosed orally q.d. or b.i.d at adose not to exceed about 500 mgs a day. The patients can be withdrawnfrom or have a decrease in the dosage of their current therapy and wouldbe maintained on treatment with the CCR2 antagonist. Alternately CCR2antagonist treatment may be used to supplement their current therapy toenhance its effectiveness in, for example, preventing plaqueprogression, stabilizing plaque that has already formed or inducingplaque regression.

Advantages of substituting or supplementing traditional agents with CCR2antagonists are numerous. Such agents may be useful, for example, topreclude progression of the plaque to a stage of instability with itsassociated risk of plaque rupture. Such agents may reduce or replace theneed for the use of cholesterol modifying drugs or HDL elevating drugs,with their attendant toxicities including, but not limited to, flushing,liver damage and muscle damage such as myopathy. Such agents may alsoreduce the need for, or prolong the period until, surgery is required toopen the vessel wall or until use of anticoagulants is required to limitdamage due to potential plaque rupture.

Labeled Compounds and Assay Methods

Another aspect of the present invention relates to fluorescent dye, spinlabel, heavy metal or radio-labeled compounds of Formula I that would beuseful not only in imaging but also in assays, both in vitro and invivo, for localizing and quantitating the chemokine receptor in tissuesamples, including human, and for identifying chemokine receptor ligandsby inhibition binding of a labeled compound. Accordingly, the presentinvention includes chemokine receptor assays that contain such labeledcompounds.

The present invention further includes isotopically-labeled compounds ofFormula I. An “isotopically” or “radio-labeled” compound is a compoundof the invention where one or more atoms are replaced or substituted byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature (i.e., naturallyoccurring). Suitable radionuclides that may be incorporated in compoundsof the present invention include but are not limited to ²H (also writtenas D for deuterium), ³H (also written as T for tritium), ¹¹C, ¹³C, ¹⁴C,¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I,¹²⁴I, ¹²⁵I and, ¹³¹I. The radionuclide that is incorporated in theinstant radio-labeled compounds will depend on the specific applicationof that radio-labeled compound. For example, for in vitro chemokinereceptor labeling and competition assays, compounds that incorporate ³H,¹⁴C, ⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound that has incorporated at least one radionuclide. In someembodiments the radionuclide is selected from the group consisting of³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. A radio-labeled compound of the invention can be usedin a screening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the radio-labeledcompound of the invention to the chemokine receptor. Accordingly, theability of a test compound to compete with the radio-labeled compoundfor binding to the chemokine receptor directly correlates to its bindingaffinity.

Kits

The present invention also includes pharmaceutical kits useful, forexample, in the treatment or prevention of chemokine-associated diseaseswhich include one or more containers containing a pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof Formula I. Such kits can further include, if desired, one or more ofvarious conventional pharmaceutical kit components, such as, forexample, containers with one or more pharmaceutically acceptablecarriers, additional containers, etc., as will be readily apparent tothose skilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, canalso be included in the kit.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

PREPARATIONS AND EXAMPLES

The compounds of the Preparations and Examples can be prepared accordingto the methods described herein and/or according to routine syntheticmethods. Example methods can be found in, for example, U.S. Ser. Nos.11/167,329 and 11/167,816, both filed Jun. 27, 2005, as well as WO2005/067502, each of which is incorporated herein by reference in itsentirety. Further, the compounds of the Examples can be tested forinhibitory activity of CCR2 or other chemokines according any one ormore of the assays described herein or are known in the art.

Preparation 1:(3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanoneStep A:

A solution of(1S,4S)-4-isopropyl-4-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopent-2-en-1-amine(3.5 g, 9.2 mmol) and 3,5-Cyclohexadiene-1,2-dione,3,5-bis(1,1-dimethylethyl)- (2.20 g, 9.99 mmol) in Methanol (85 mL) wasstirred at room temperature for 30 minutes. Tetrahydrofuran (85 mL) and1N HCl (10 mL) were added and the resulting mixture was stirredovernight at room temperature. The mixture was diluted with water andthe organics evaporated. The remaining aqueous was made basic with 1NNaOH and extracted with EtOAc three times. The combined extracts weredried (Magnesium sulfate), filtered, and concentrated in vacuo. Thecrude residue was purified by flash column chromatography (1:1EtOAc/Hexanes) to yield (3.16 g, 90%) of the title compound. MScalculated for C₁₉H₂₂F₃N₃O₂: (M+H) 382; found 382.1.

Step B:

A mixture of the product from Step A (3.15 g, 8.26 mmol), palladium oncarbon (10%, 632 mg), triethylamine (1.2 ml, 8.26 mmol), and methanol(32 ml) was hydrogenated at 40 psi for 90 minutes. The mixture wasfiltered through Celite, washing with DCM. The filtrates wereconcentrated in vacuo to afford 3.0 g (96%) of the title compound as atan solid. MS calculated for C₁₉H₂₄F₃N₃O₂: (M+H) 384; found 384.1.

Preparation 1A:(3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanone

The title compound was prepared in a fashion similar to that forPreparation 1 starting from(1S,4S)-4-Isopropyl-4-(4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-ylcarbonyl)cyclopent-2-en-1-amine.MS calculated for C₁₈H₂₃F₃N₄O₂: (M+H) 385; found 385.1.

Example 14-{[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl)carbonyl)cyclopentyl]amino}-1-(5-pyrimidin-2-ylpyridin-2-yl}cyclohexanol

To a solution of((1S,3R)-3-amino-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone(50 mg, 0.13 mmol) in DCM (2 mL) was added4-hydroxy-4-(5-(pyrimidin-2-yl)pyridin-2-yl)cyclohexanone (1.5 equiv)and sodium triacetoxyborohydride (1.5 equiv). The mixture was stirreduntil complete, portioned and the aqueous phase extracted with ethylacetate. The combined organic layers were dried over sodium sulfate.Chromatography gave the title compound as a white powder afterlypholization. MS calculated for C₃₂H₄₂F₃N₇O₂: (M+H) 638; found 638.3.

Example 2 ethyl4-{[(1R3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}-3-methoxypiperidine-1-carboxylate

A. Preparation of tert-butyl3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate

The title compound was prepared by taking tert-Butyl4-Oxo-1-piperidinecarboxylate (2 g, 0.01 mol) in Methanol (19 mL, 0.47mol) and adding Potassium hydroxide (1.3 g, 0.024 mol;) at 0° C. To thismixture was added Iodine (2.8 g, 0.011 mol) in Methanol (21 mL, 0.52mol) dropwise over 30 min to keep the internal temperature close to 0°C. The reaction was then allowed to warm to ambient temperature for 2 h.The reaction was then concentrated in vacuo and the residue wasdissolved in toluene (20 mL) and filtered. The filtrate was purified viaflash chromatography to afford an oil (1.8 g, 70%) which has the sameNMR as described in Zacuto, Michael J.; Cai, Dongwei., TetrahedronLetters, 2005, 46(3), 447-450. ¹H NMR (CD3OD, 400 MHz) δ 4.06-4.00 (m,1H), 3.99-3.91 (m, 1H), 3.80-3.73 (m, 1H), 3.29 (s, 3H), 3.28 (s, 3H),3.22-3.10 (br m, 1H), 2.95-2.80 (br m, 1H), 1.91-1.77 (m, 2H), 1.50 (s,9H).

B. Preparation of tert-butyl 3,4,4-trimethoxypiperidine-1-carboxylate

The title compound was prepared by taking tert-butyl3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (702 mg, 0.00269 mol) inTetrahydrofuran (10 mL, 0.1 mol) at 0° C. and adding in Potassiumtert-butoxide (15 mL, 0.015 mol). The reaction was stirred for 20 minand then Dimethyl sulfate (0.56 mL, 0.006 mol) was added and thetemperature raised to ambient temperature. After stirring overnight thereaction mixture was poured into water and ethyl acetate. The organiclayers were separated, dried and concentrated in vacuo to afford an oilwhich was used as-is (424 mg, 99%) MS calculated for C₁₃H₂₅NO₅; (M+H)276; found 276.1.

C. Preparation of 3,4,4-trimethoxypiperidine

The title compound was prepared by taking tert-butyl3,4,4-trimethoxypiperidine-1-carboxylate (424 mg, 0.00154 mol) inMethylene chloride (10 mL, 0.2 mol) and adding Trifluoroacetic Acid (1mL, 0.02 mol). The reaction was stirred for 3 h. The solvent was removedin vacuo and the crude taken to the next step (270 mg, 99%). MScalculated for C₈H₁₇NO₃; (M+H) 176; found 176.1.

D. Preparation of ethyl 3,4,4-trimethoxypiperidine-1-carboxylate

The title compound was prepared by taking 3,4,4-trimethoxypiperidine(150 mg, 0.00086 mol) in Methylene chloride (10 mL, 0.2 mol) and addingEthyl chloroformate (0.098 mL, 0.0010 mol) and Triethylamine (0.24 mL,0.0017 mol). The reaction was sitrred overnight and then quenched withNaHCO₃. The crude was obtained by evaporating the organic layer and wastaken to the next step as-is (210 mg, 99%). MS calculated for C₁₁H₂₁NO₅:(M+H) 248; found 248.1.

E. Preparation of ethyl 3-methoxy-4-oxopiperidine-1-carboxylate

The title compound was prepared by taking3,4,4-trimethoxypiperidine-1-carboxylate (210 mg, 0.00085 mol) inMethanol (5 mL, 0.1 mol) and adding 4 M of Hydrogen chloride in1,4-dioxane (5 mL). The reaction was allowed to stir for 4 h at ambienttemperature. The residue obtained by removing the solvent in vacuo wasused in the next step as-is (170 mg, 99%). MS calculated for C₉H₁₅NO₄:(M+H) 202; found 202.1.

F. Preparation of ethyl4-{[(1S,4S)-4-isopropyl-4-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopent-2-en-1-yl]amino}-3-methoxypiperidine-1-carboxylate

The title compound was prepared by taking ethyl3-methoxy-4-oxopiperidine-1-carboxylate (148 mg, 0.000737 mol) inMethylene chloride (3 mL, 0.04 mol) and adding(1S,4S)-4-isopropyl-4-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopent-2-en-1-amine(0.31 g, 0.00081 mol;), Triethylamine (0.8 mL, 0.006 mol;) and Sodiumtriacetoxyborohydride (0.312 g, 0.00147 mol). The reaction was stirredovernight. The reaction was quenched with (20 mL) NaOH and extractedwith (3×10 mL) CH₂Cl₂. The organic layers were collected, dried overMgSO₄ and concentrated in vacuo. The crude was taken on to the next stepas-is (410 mg, 98%). MS calculated for C₂₈H₄₀F₃N₅O₄: (M+H) 568; found568.1.

G. Preparation of4-{[(1R3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}-1-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanol

The title compound was prepared taking ethyl4-{[(1S,4S)-4-isopropyl-4-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopent-2-en-1-yl]amino}-3-methoxypiperidine-1-carboxylate(410 mg, 0.00072 mol) in Methanol (10 mL, 0.3 mol) and PalladiumHydroxide (1:4, Palladium hydroxide:Tetracarbon, 150 mg). The reactionmixture was pressurized to 52 PSI and shaken for 4 hrs. The solvent wasremoved and the material purified via prep LCMS to afford the set ofdiastereomers as a white powder after lypholization (120 mg, 29%). MScalculated for C₂₈H₄₂F₃N₅O₄: (M+H) 570; found 570.1.

Example 3 methyl4-{[(1R3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}-3-methoxypiperidine-1-carboxylate

The title compound was prepared in a fashion similar to that for Example2 starting from methyl 3,4,4-trimethoxypiperidine-1-carboxylate (150 mg,0.00086 mol) to afford the desired compounds as white powder afterlypholization (100 mg, 20%). MS calculated for C₂₇H₄₀F₃N₅O₄: (M+H) 556;found 556.1.

Example 4((1S,3R)-3-(3-oxa-bicyclo[3.3.1]nonan-9-ylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

The title compound was prepared in a fashion similar to that for Example1 employing, in the reductive alkylation,3-oxabicyclo[3.3.1]non-5-en-9-one, followed by hydrogenation of withPd/C (5%) in Ethyl Acetate. MS calculated for C₂₈H₃₄F₃N₅O₃: (M+H)509.3025; found 509.2.

Example 5(1R,3S)—N-[(5-chloro-2-thienyl)methyl]-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example1 employing, in the reductive alkylation,5-chlorothiophene-2-carbaldehyde. MS calculated for C₂₄H₃₀ClF₃N₄OS:(M+H) 515.1781; found 515.185.

Example 6(1R,3S)-3-isopropyl-N-[(1-pyridin-3-yl-1H-pyrrol-2-yl)methyl]-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation,1-(pyridin-3-yl)-1H-pyrrole-2-carbaldehyde. MS calculated forC₂₉H₃₅F₃N₆O: (M+H) 541.2824.

Example 7(1R,3S)—N-[(1-ethyl-1H-pyrazol-4-yl)methyl]-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation,1-ethyl-1H-pyrazole-4-carbaldehyde. MS calculated for C₂₅H₃₆F₃N₆O: (M+H)493.2824; found 493.2997.

Example 8(1R,3S)-3-isopropyl-N-(quinolin-6-ylmethyl)-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, quinoline-7-carbaldehyde. MScalculated for C₂₉H₃₄F₃N₅O: (M+H) 526.2715; found 526.2792.

Example 97-({[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}methyl)-1H-pyrido[23-b][14]oxazin-2(3H)-one

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation,2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbaldehyde. MScalculated for C₂₇H₃₃F₃N₆O₃: (M+H) 547.2566; found 547.2681.

Example 10(1R,3S)—N-(24-dimethoxybenzyl)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, 2,4-dimethoxybenzaldehyde. MScalculated for C₂₈H₃₇F₃N₄O₃: (M+H) 535.2818; found 535.2701.

Example 11N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-1-pyrimidin-2-ylpiperidin-3-amine

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 1-(pyrimidin-2-yl)piperidin-3-one. MS calculated forC₂₈H₃₈F₃N₇O: (M+H) 546.309; found 546.3195.

Example 121-but-2-yn-1-yl-5-{[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}azepan-2-one

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 1-(but-2-ynyl)azepane-2,5-dione. MS calculated forC₂₉H₄₀F₃N₅O₂: (M+H) 548.3134; found 548.3223.

Example 13N-isopropyl-3-(2-{[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}cyclopentyl)propanamide

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, N-isopropyl-3-(2-oxocyclopentyl)propanamide. MS calculatedfor C₃₀H₄₆F₃N₅O₂: (M+H) 566.3604; found 566.3769.

Example 14N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]indan-2-amine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, 1H-inden-2(3H)-one. MScalculated for C₂₈H₃₅F₃N₄O: (M+H) 501.2763; found 501.2851.

Example 15N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydro-2H-thiopyran-4-amine11-dioxide

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, tetrahydro-4H-thiopyran-4-one1,1-dioxide. MS calculated for C₂₄H₃₅F₃N₄O₃S: (M+H) 517.2382; found517.2496.

Example 16(1R,3S)—N-cyclopentyl-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, cyclopentanone. MS calculatedfor C₂₄H₃₅F₃N₄O: (M+H) 453.2763; found 453.2859.

Example 173-(2-{[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}cyclopentyl)-N-propylpropanamide

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 3-(2-oxocyclopentyl)-N-propylpropanamide. MS calculated forC₃₀H₄₆F₃N₅O₂: (M+H) 566.3604; found 566.3762.

Example 186,8-difluoro-N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-1234-tetrahydronaphthalen-2-amine

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 6,8-difluoro-3,4-dihydronaphthalen-2(1H-one. MS calculatedfor C₂₉H₃₅F₅N₄O: (M+H) 551.2731; found 551.2922

Example 19N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-1234-tetrahydronaphthalen-2-amine

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 3,4-dihydronaphthalen-2(1H)-one. MS calculated forC₂₉H₃₇F₃N₄O: (M+H) 515.2919; found 515.2982.

Example 202,5-anhydro-1,3,4-trideoxy-3-{[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}pentitol

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 2-methyl-dihydrofuran-3(2H)-one. MS calculated forC₂₄H₃₅F₃N₄O₂: (M+H) 469.2712; found 469.2931.

Example 21N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-35-dimethyltetrahydro-2H-pyran-4-amine

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 3,5-dimethyl-tetrahydropyran-4-one. MS calculated forC₂₆H₃₉F₃N₄O₂: (M+H) 497.3025; found 497.3311.

Example 22(1R,3S)-3-isopropyl-N-[1-methyl-3-(1H-pyrazol-1-yl)propyl]-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, 4-(1H-pyrazol-1-yl)butan-2-one. MS calculated forC₂₆H₃₇F₃N₆O: (M+H) 507.2981; found 507.2992.

Example 23N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydrofuran-3-amine

The title compound, as a mixture of diastereomers, was prepared in afashion similar to that for Example 2 employing, in the reductivealkylation, dihydrofuran-3(2H)-one. MS calculated for C₂₃H₃₃F₃N₄O₂:(M+H) 455.2556; found 455.2064.

Example 24N-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]-N-methyltetrahydrofuran-3-amine

To a solution ofN-[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]tetrahydrofuran-3-amine(160 mg) in 5 mL of methanol was added a solution of formaldehyde (10equiv) followed by NaCNBH3 (3 equiv). Once the reaction was complete,the volatiles were removed and the residue taken in ethyl acetate. Theethyl acetate layer was washed with aqueous NaOH (2.5N). The organiclayer was dried over sodium sulfate, filtered and evaporated. Theresidue was purified by chromatography to give the title compound (126mg). MS calculated for C₂₄H₃₅F₃N₄O₂: (M+H) 469.2712; found 469.2817.

Example 25(1R,3S)—N-(34-dimethoxybenzyl)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, 3,4-dimethoxybenzaldehyde. MScalculated for C₂₈H₃₇F₃N₄O₃: (M+H) 535.2818; found 535.2940.

Example 26(1R,3S)—N-(1H-indol-5-ylmethyl)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, 1H-indole-5-carbaldehyde. MScalculated for C₂₈H₃₄F₃N₅O; (M+H) 514.2715; found 514.2752.

Example 274-({[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}methyl)phenol

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, 4-hydroxybenzaldehyde. MScalculated for C₂₆H₃₃F₃N₄O₂: (M+H) 491.2556; found 491.2601.

Example 28(1R,3S)—N-(4-fluorobenzyl)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation, 4-fluorobenzaldehyde. MScalculated for C₂₆H₃₂F₄N₄O: (M+H) 493.2512; found 493.2605.

Example 295-({[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}methyl)-2-methoxyphenol

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation,3-hydroxy-4-methoxybenzaldehyde. MS calculated for C₂₇H₃₅F₃N₄O₃: (M+H)521.2661; found 521.2747.

Example 306-({[(1R,3S)-3-isopropyl-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentyl]amino}methyl)-2H-14-benzoxazin-3(4H)-one

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation,3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbaldehyde. MS calculatedfor C₂₈H₃₄F₃N₅O₃: (M+H) 546.2614; found 546.2679.

Example 31(1R,3S)-3-isopropyl-N-(3-methoxy-4-methylbenzyl)-3-({4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}carbonyl)cyclopentanamine

The title compound was prepared in a fashion similar to that for Example2 employing, in the reductive alkylation,3-methoxy-4-methylbenzaldehyde. MS calculated for C₂₈H₃₄F₃N₅O₃: (M+H)519.2869; found 519.2986.

Example 32((1S,3R)-3-(benzylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 33((1S,3R)-3-(4-chlorobenzylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 34((1S,3R)-3-(4-methoxybenzylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 35((1S,3R)-3-(4-hydroxy-3-methylbutan-2-ylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 36((1S,3R)-3-(4-hydroxy-4-methylpentan-2-ylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)methanone

Example 37((1S,3R)-3-(2-(chloromethyl)-3-hydroxy-2-methylpropylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)methanone

Example 38((1S,3R)-1-isopropyl-3-((tetrahydro-2H-pyran-4-yl)methylamino)cyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)-5,6-dihydropyridin-1(2H)-yl)methanone

Example 39((1S,3R)-1-isopropyl-3-(methyl(neopentyl)amino)cyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 40N-((1R,3S)-3-isopropyl-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentyl)benzenesulfonamide

Example 41((1S,3R)-1-isopropyl-3-(1-phenylethylamino)cyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 42((1S,3R)-1-isopropyl-3-(1-phenylpropylamino)cyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 43((1S,3R)-3-(diethylamino)-1-isopropylcyclopentyl)(4-(5-(trifluoromethyl)pyridin-3-yl)-5,6-dihydropyridin-1(2H)-yl)methanone

Example 44((1S,3R)-1-isopropyl-3-(1-(tetrahydro-2H-pyran-4-yl)ethylamino)cyclopentyl)(4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)methanone

Example 45((1S,3R)-1-isopropyl-3-((3-methoxy-tetrahydro-2H-pyran-4-yl)methylamino)cyclopentyl)(4-(6-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 46((1S,3R)-3-(1,2-diphenylethylamino)-1-isopropylcyclopentyl)(4-(6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)methanone

Example 47((1S,3R)-1-isopropyl-3-(phenethylamino)cyclopentyl)(4-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)piperazin-1-yl)methanone

Example 483-fluoro-N-((1R,3S)-3-isopropyl-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentyl)benzenesulfonamide

Example 493-((1R,3S)-3-(2-hydroxypropan-2-yl)-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentylamino)-2,2-dimethylpropanoicacid

Example 50((1S,3R)-1-isopropyl-3-(pyridin-3-ylmethylamino)cyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 51((1S,3R)-3-(3-hydroxypropylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 52((1S,3R)-3-(benzyl(isopropyl)amino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 53N-((1R,3S)-3-isopropyl-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentyl)benzamide

Example 54N-((1R,3S)-3-isopropyl-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentyl)cyclohexanecarboxamide

Example 55N-((1R,3S)-3-isopropyl-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentyl)-2-(tetrahydro-2H-pyran-4-yl)acetamide

Example 56((1S,3R)-1-isopropyl-3-(naphthalen-2-ylmethylamino)cyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 57((1S,3R)-3-(4-hydroxy-4-(thiazol-2-yl)cyclohexylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)Pyridin-2-yl)piperazin-1-yl)methanone

Example 58((1S,3R)-3-(4-phenoxybenzylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 59((1S,3R)-3-(3,4-dimethoxybenzylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 60((1S,3R)-3-(3,5-bis(trifluoromethyl)benzylamino)-1-isopropylcyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example 61N-((1R,3S)-3-isopropyl-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentyl)methanesulfonamide

Example 62N-((1R,3S)-3-isopropyl-3-(1-(4-(trifluoromethyl)pyridin-2-yl)piperazine-4-carbonyl)cyclopentyl)-4-(trifluoromethyl)benzenesulfonamide

Example 63((1S,3R)-1-isopropyl-3-(neopentylamino)cyclopentyl)(4-(4-(trifluoromethyl)pyridin-2-yl)piperazin-1-yl)methanone

Example A CCR2 In Vitro Assays

The capacity of the novel compounds of the invention to antagonizechemokine receptor (e.g., CCR2) function can be determined using asuitable screen (e.g., high through-put assay). For example, an agentcan be tested in an extracellular acidification assay, calcium fluxassay, ligand binding assay or chemotaxis assay (see, for example,Hesselgesser et al., J Biol. Chem. 273(25):15687-15692 (1998); WO00/05265 and WO 98/02151).

In a suitable assay, a CCR2 protein which can be isolated orrecombinantly derived is used which has at least one property, activityor functional characteristic of a mammalian CCR2 protein. The specificproperty can be a binding property (to, for example, a ligand orinhibitor), a signalling activity (e.g., activation of a mammalian Gprotein, induction of rapid and transient increase in the concentrationof cytosolic free calcium [Ca⁺⁺]i, cellular response function (e.g.,stimulation of chemotaxis or inflammatory mediator release byleukocytes), and the like.

In an example binding assay, a composition containing a CCR2 protein orvariant thereof is maintained under conditions suitable for binding. TheCCR2 receptor is contacted with a compound to be tested, and binding isdetected or measured.

In an example cell-based assay, cells are used which are stably ortransiently transfected with a vector or expression cassette having anucleic acid sequence which encodes the CCR2 receptor. The cells aremaintained under conditions appropriate for expression of the receptorand are contacted with an agent under conditions appropriate for bindingto occur. Binding can be detected using standard techniques. Forexample, the extent of binding can be determined relative to a suitablecontrol. Also, a cellular fraction, such as a membrane fraction,containing the receptor can be used in lieu of whole cells.

Detection of binding or complex formation in an assay can be detecteddirectly or indirectly. For example, the agent can be labeled with asuitable label (e.g., fluorescent label, label, isotope label, enzymelabel, and the like) and binding can be determined by detection of thelabel. Specific and/or competitive binding can be assessed bycompetition or displacement studies, using unlabeled agent or a ligandas a competitor.

The CCR2 antagonist activity of compounds of the invention can bereported as the inhibitor concentration required for 50% inhibition(IC₅₀ values) of specific binding in receptor binding assays using¹²⁵I-labeled MCP-1, as ligand, and Peripheral Blood Mononuclear Cells(PBMCs) prepared from normal human whole blood via density gradientcentrifugation. Specific binding is preferably defined as the totalbinding (e.g., total cpm on filters) minus the non-specific binding.Non-specific binding is defined as the amount of cpm still detected inthe presence of excess unlabeled competitor (e.g., MCP-1).

Example B Binding Assay

Human PBMCs are used to test compounds of the invention in a bindingassay. For example, 200,000 to 500,000 cells are incubated with 0.1 to0.2 nM ¹²⁵I-labeled MCP-1, with or without unlabeled competitor (10 nMMCP-1) or various concentrations of compounds to be tested. ¹²⁵I-labeledMCP-1, are prepared by suitable methods or purchased from commercialvendors (Perkin Elmer, Boston Mass.). The binding reactions areperformed in 50 to 250 μL of a binding buffer consisting of 1M HEPES pH7.2, and 0.1% BSA (bovine serum albumin), for 30 min at roomtemperature. The binding reactions are terminated by harvesting themembranes by rapid filtration through glass fiber filters (Perkin Elmer)which is presoaked in 0.3% polyethyleneimine or Phosphate BufferedSaline (PBS). The filters were rinsed with approximately 600 μL ofbinding buffer containing 0.5 M NaCl or PBS, then dried, and the amountof bound radioactivity is determined by counting on a Gamma Counter(Perkin Elmer).

Active compounds of the present invention have IC₅₀ values less thanabout 3000 nM.

EXAMPLE NUMBER CCR2 IC₅₀ nM 1 19.8 2 62.0 and 391 3 66.9 and 362 5 616 7617 8 476 9 338 10 519 11 420 12 660 13 273 14 74.8 15 541 16 227 17 19018 51.7 19 138 20 80.6 21 10.1 22 504 23 157 24 181 25 500 26 273 27 47028 389 29 736 30 364 31 334

Example C Chemotaxis Assay

The capacity of compounds of the invention to antagonize CCR2 functioncan be determined in a leukocyte chemotaxis assay using human peripheralblood mononuclear cells, in a modified Boyden Chamber (Neuro Probe).500,000 cells in serum free DMEM media (In Vitrogen) are incubated withor without the inhibitors and warmed to 37° C. The chemotaxis chamber(Neuro Probe) is also prewarmed. Then 400 μL of warmed 10 nM MCP-1 isadded to the bottom chamber in all wells except the negative controlwhich has DMEM added. An 8 micron membrane filter (Neuro Probe) isplaced on top and the chamber lid is closed. Cells are then added to theholes in the chamber lid which are associated with the chamber wellsbelow the filter membrane. The whole chamber is incubated at 37° C., 5%CO₂ for 30 minutes. The cells are then aspirated off, the chamber lidopened, and the filter gently removed. The top of the filter is washed 3times with PBS and the bottom is left untouched. The filter is air driedand stained with Wright Geimsa stain (Sigma). Filters are counted bymicroscopy. The negative control wells serve as background and aresubtracted from all values. Antagonist potency is determined bycomparing the number of cells that migrate to the bottom chamber inwells which contained antagonist, to the number of cells which migrateto the bottom chamber in MCP-1 control wells.

Active compounds of the invention have IC₅₀ values less than about 3000nM.

Example D CCR5 Expression

A leukophoresis (Biological Specialty, Colmar, Pa.) is obtained fromnormal, drug free donors and peripheral blood mononuclear cells (PBMCs)are isolated via density gradient centrifugation. Monocytes are furtherisolated via centrifugal elutriation. After being washed, the monocytesare re-suspended at 10⁶ cells/ml with RPMI (Invitrogen, Carlsbad,Calif.) supplemented with 10% FBS (Hyclone, Logan, Utah) and 10-20 ng/mLof recombinant human IL-10 (R&D systems, Minneapolis, Minn.) andincubated in the same medium at 37° C. with 5% CO₂ for 24-48 hr. CCR5expression on the IL-10—treated monocytes is then verified by stainingthe cells with a PE-conjugated anti-human CCR5 antibody ((PharMingen,San Diego, Calif.), followed by FACS analysis using FACSCalibur (BDBiosciences, Bedford, Mass.).

Example E CCR5 Binding Assay

In a 96 well MultiScreen™ filter plate (Millipore Systems, Billerica,Mass.), 3×10⁵ IL-10-treated monocytes in 150 pt RPMI (Invitrogen,Carlsbad, Calif.) with 20 mM HEPES (Invitrogen, Carlsbad, Calif.) and0.3% BSA (Sigma, St Louis, Mo.) are incubated at room temperature for 1hr. with 0.2 nM ¹²⁶I-MIP-113 (Perkin Elmer, Boston, Mass.) and a seriesconcentrations of compound of the invention. Non-specific binding isdetermined by incubating the cells with 0.3 μM MIP-13 (R&D Systems,Minneapolis, Minn.). The binding reaction is terminated by harvestingthe cells onto the filter in the plate on a vacuum manifold (MilliporeSystems, Billerica, Mass.). The filter is then washed 5 times with RPMI(Invitrogen, Carlsbad, Calif.) supplemented with 20 mM HEPES(Invitrogen, Carlsbad, Calif.), 0.3% BSA (Sigma, St Louis, Mo.) and 0.4M NaCl on the vacuum manifold, air dried, and peeled from the plate. Thefilter dishes corresponding to the sample wells in a filter plate arepunched out using the Millipore Punch System (Millipore Systems,Billerica, Mass.). The amount of bound radioactivity on each filter dishis determined by counting on a gamma counter. Specific binding isdefined as the total binding minus the non-specific binding. The bindingdata are evaluated with Prism (GraphPad Software, San Diego, Calif.).Active compounds have a binding affinity of about 1 μM or less accordingto this assay.

Example F HIV-1 Entry Assay

Replication defective HIV-1 reporter virions are generated bycotransfection of a plasmid encoding the NL4-3 strain of HIV-1 (whichhas been modified by mutation of the envelope gene and introduction of aluciferase reporter plasmid) along with a plasmid encoding one ofseveral HIV-1 envelope genes as described by, for example, Connor et al,Virology, 206 (1995), 935-944. Following transfection of the twoplasmids by calcium phosphate precipitation, the viral supernatants areharvested on day 3 and a functional viral titer determined. These stocksare then used to infect U87 cells stably expressing CD4 and thechemokine receptor CCR5 which have been preincubated with or withouttest compound. Infections are carried out for 2 hours at 37° C., thecells washed and media replaced with fresh media containing compound.The cells are incubated for 3 days, lysed and luciferase activitydetermined. Results are reported as the concentration of compoundrequired to inhibit 50% of the luciferase activity in the controlcultures.

Example G HIV-1 Replication Assay in MT-4 Cells

Inhibition of HIV-1 NL4.3 (or III_(B)) replication assays can be carriedout as previously described (Bridger, et al., J. Med. Chem.,42:3971-3981 (1999); De Clercq, et al., Proc. Natl. Acad. Sci.89:5286-5290 (1992); De Clercq, et al., Antimicrob. Agents Chemother.38:668-674 (1994); Bridger, et al. J. Med. Chem. 38:366-378 (1995)). Tosummarize, anti-HIV activity and cytotoxicity measurements are carriedout in parallel and are based on the viability of MT-4 cells that areinfected with HIV in the presence of various concentrations of the testcompounds. After the MT-4 cells are allowed to proliferate for 5 days,the number of viable cells are quantified by a tetrazolium-basedcalorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) procedure in 96-well microtrays. Results can be quanititedto yield EC₅₀ values which represent the concentration required toprotect 50% of the virus-infected cells against viral cytopathicity.

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference, including patents, patentapplications, and publications, cited in the present application isincorporated herein by reference in its entirety.

1-57. (canceled)
 58. A composition comprising a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier, wherein; a dashed line indicates anoptional bond; W is:

V is N, NO or CR⁵; X is N, NO or CR²; Y is N, NO or CR³; Z is N, NO orCR⁴; wherein no more than one of V, X, Y and Z is NO; L is C₁₋₄alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, C(O), C(O)NR⁹, S(O)NR⁹,S(O)₂, or S(O)₂NR⁹, R^(A), R^(A1), R^(B) and R^(B1) are each,Independently, HOH, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, heterocyclyl, carbocyclyl,NR¹⁰R¹², NR¹⁰CO₂R¹¹; NR¹⁰CONR¹⁰R¹², NR¹⁰S0₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, CN,CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR¹⁰, SOR¹⁰, SO₂R¹⁰, or SO₂—NR¹⁰R¹²; R¹ is C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₀₋₆alkyl)-O-(C1_(—)6alkyl), —(C₀₋₆alkyl)-S(C₁₋₆ alkyl), —(C₀₋₆alkyl)-(C₃₋₇ cycloalkyl)-(C₀₋₆alkyl), OH, OR¹⁰, SR¹⁰, COR¹¹, CO₂R¹⁰, CONR¹⁰R¹², carbocyclyl,heterocyclyl, CN, NR¹⁰R¹², NR¹⁰—SO₂R¹⁰, NR10COR¹⁰, NR¹⁰CO₂R¹⁰,NR¹⁰CONR¹², CR¹⁰R¹¹CO₂R¹⁰ or CR¹⁰R¹¹0COR¹⁰; R², R³, R⁴, R⁵ and R⁶ areeach, independently, H, OH, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, C₁₋₆ thioalkoxy, NR¹⁰R¹², NR¹⁰CO₂R¹¹, NR¹⁰CONR¹⁰R¹²,NR¹⁰SO₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, heterocyclyl, carbocyclyl, carbocyclyloxy,heterocyclyloxy, CN, NO₂, COR¹¹, CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR^(1O),SOR^(1O)SO₂R¹⁰; or SO₂—NR¹⁰R¹²; R⁷ is H or C₁₋₈ alkyl optionallysubstituted by 1, 2, 3, 4, 5 or 6 substituents independently selectedfrom halo, C₁₋₁₀ haloalkyl, Cy, CN, NO₂, OR^(a), C(O)R^(b),C(O)NR^(C)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(C)R^(d), NR^(c)R^(d),NR^(C)C(O)R^(b), NR^(C)C(O)NR^(C)R^(d), NR^(C)C(O)OR^(a), S(O)R^(b),S(O)NR^(C)R^(d), S(O)₂R^(b), NR^(C)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); orR⁷ is H, C₁₋₈alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, —O—C₁₋₆alkyl, —NR^(12a)R^(12a),—NR^(12a)COR^(13a), —NR^(12a)SO₂R^(14a), COR^(11a), —CONR^(12a)R^(12a),phenyl and heterocycle, where the alkyl, phenyl, and heterocycle areunsubstituted or substituted with 1-3 substituents selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, trifluoromethyl,and —SO₂C₁₋₆alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, halo, —O—C₁₋₆ alkyl, CN,—NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a), —COR^(11a),—CONR^(12a)R^(12a), phenyl and heterocycle, where the alkyl, phenyl, andheterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy, —C0₂H,—C0₂—C₁₋₆alkyl, and trifluoromethyl; or R⁷ is H, C₁₋₆alkyl unsubstitutedor substituted with 1-3 substituents selected from: halo, hydroxy,—C0₂H, —C0₂C₁₋₆alkyl, and —O—C¹⁻³alkyl; R⁸ is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl,or heterocycloalkyl, wherein said C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from oxo, hydroxy, halo, C₁₋₄ alkyl,C₁₋₄alkoxy, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′, —(C₁₋₄ alkyl)-Cy′, CN, NO₂,—(CH₂)_(q)—ORa′, —(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)^(b′),—(CH₂)_(q)—C(O)NR^(C′)R^(d)′, —(CH₂)_(q)—C(O)OR^(a′),—(CH₂)_(q)—S(O)R^(b′), —(CH₂)_(q)—S(O)₂R^(b′), and—(CH₂)_(q)—S(O)₂NR^(c′) R^(d′); or R⁸ is selected from C₁₋₁₀alkyl,—SO₂C₁₋₁₀alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5substituents selected from: hydroxy, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,CN, —NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),—COR^(12a), S0₂R^(14a), heterocycle, ═O (where the oxygen is connectedvia a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxyand heterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —COR^(11a), —CN,—NR^(12a)R^(12a), —S0₂R^(14a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),and —CONR^(12a)R^(12a), where the alkyl and alkoxy are optionallysubstituted with 1-5 fluoro; or R⁸ is a group of formula:

Y and Z are independently selected from —O—, —NR^(12b), —S—, —SO—, SO₂—,—CR^(12b)R^(12b)—, NSO₂R^(14b)—, —NCOR^(13b)—, —CR^(12b)COR^(11b)—,—CR^(12b)OCOR^(13b)—, —C— and —CO—; R^(8a) is selected from: hydrogen,C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b), fluoro, —O—C₁₋₃alkylunsubstituted or substituted with 1-3 fluoro, C₃₋₆cycloalkyl,—O—C₃₋₆cycloalkyl, hydroxy, —COR^(11b), —OCOR^(13b); or R⁷ and R^(8a)together are C₂₋₄alkyl or C₀₋₂alkyl-O—C₁₋₃alkyl, forming a 5-7 memberedring; R^(9a) is selected from: hydrogen, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 substituents selected from fluoro, C₁₋₃alkoxy,hydroxy and —COR^(11b), COR^(11b), hydroxy and —O—C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and —COR^(11b); or R^(8a) and R^(9a) together areC₁₋₄alkyl or C₀₋₃alkyl-O—C₀₋₃alkyl, forming a 3-6 membered ring; R^(10a)is selected from: hydrogen, hydroxy, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 fluoro, fluoro, —O—C₃₋₆cycloalkyl and —O—C₁₋₃alkylunsubstituted or substituted with 1-6 fluoro; or R^(8a) and R^(ma)together are C₂₋₃alkyl, forming a 5-6 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy; orR^(8a) and R^(10a) together are O—C₁₋₂alkyl-O—C₁₋₂alkyl, forming a 6-8membered ring, where said alkyl is unsubstituted or substituted with 1-3substituents independently selected from halo, hydroxy, —COR^(11b),C₁₋₃alkyl and C₁₋₃alkoxy; or R^(8a) and R^(10a) together are—O—C₁₋₂alkyl-O—, forming a 6-7 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, —COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy;R^(11a) and R^(11b) are independently selected from: hydroxy, hydrogen,C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl, phenyl and C₃₋₆cycloalkyl, where saidalkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; R^(12a) and R^(12b) are independently selected from:hydrogen, hydroxy, C₁₋₆alkyl, benzyl, phenyl, C₃₋₆ cycloalkyl, where thealkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; or R^(12a) and R^(12b) are selected from: C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and COR^(11b), fluoro, —O—C₁₋₃alkyl unsubstituted orsubstituted with 1-6 fluoro, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, hydroxy,—O—C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b); R^(13a) and R^(13b) areindependently selected from: hydrogen, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy,—CO₂H, —CO₂—C₁₋₆alkyl, and trifluoromethyl; R^(14a) and R^(14b)independently selected from: hydroxy, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H,—CO₂—C₁₋₆alkyl, and trifluoromethyl; Cy and Cy′ are, independently,aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromoxo, hydroxy, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(C″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(C″)R^(d″), NR^(c″)R^(d″),NR^(C″)C(O)R^(b″), NR^(C″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(C″)R^(b″),and S(O)₂NR^(C″)R^(d″), aryl, or heteroaryl, cycloalkyl, orheterocycloalkyl; R⁹ is H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R¹⁰ is H, C₁₋₆alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl, wherein said C₁₋₆ alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R¹¹ is H, OH,C₁₋₆alkyl, C₁₋₆ alkoxy, benzyl, phenyl, benzyloxy, phenyloxy,C₃₋₆cycloalkyl or C₃₋₆cycloalkyloxy, wherein said C₁₋₆alkyl, C₁₋₆alkoxy,benzyl, phenyl, benzyloxy, phenyloxy, C₃₋₆cycloalkyl orC₃₋₆cycloalkyloxy, is optionally substituted with 1, 2 or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, CO₂H,CO₂—(C₁₋₆alkyl) and CF₃; R¹² is H, C¹⁻⁶alkyl, benzyl, phenyl, or C³⁻⁶cycloalkyl, wherein said C₁₋₆alkyl, benzyl, phenyl, or C₃₋₆cycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R^(a), R^(a′) and R^(a″) are,independently, H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R^(b), R^(b′) and R^(b″) are, independently, H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; R^(C) and R^(d) are, independently, H, C₁₋₁₀alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; or R^(C) and R^(d) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;R^(c)′ and R^(d′) are, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;or R^(C′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; R^(C″) and R^(d″) are,independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R^(C″) and R^(d″)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; m is 0, 1, or 2; n is 0 or 1; p is 0 or 1; and qis 0, 1, 2, or
 3. 59. A method of modulating activity of a chemokinereceptor comprising contacting said chemokine receptor with a compoundof Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, wherein; adashed line indicates an optional bond; W is:

V is N, NO or CR⁵; X is N, NO or CR²; Y is N, NO or CR³; Z is N, NO orCR⁴; wherein no more than one of V, X, Y and Z is NO; L is C₁₋₄alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, C(O), C(O)NR⁹, S(O)NR⁹,S(O)₂, or S(O)₂NR⁹, R^(A), R^(A1), R^(B) and R⁸¹ are each,Independently, HOH, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, heterocyclyl, carbocyclyl,NR¹⁰R¹², NR¹⁰CO₂R¹¹; NR¹⁰CONR¹⁰R¹², NR¹⁰SO₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, CN,CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR¹⁰, SOR¹⁰, SO₂R¹⁰, or SO₂—NR¹⁰R¹²; R¹ is C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₀₋₆alkyl)-0-(C1_(—)6alkyl), —(C₀₋₆alkyl)-S(C₁₋₆ alkyl), —(C₀₋₆alkyl)-(C₃₋₇ cycloalkyl)-(C₀₋₆alkyl), OH, OR¹⁰, SR¹⁰, COR¹¹, CO₂R¹⁰, CONR¹⁰R¹², carbocyclyl,heterocyclyl, CN, NR¹⁰R¹², NR¹⁰—SO₂R¹⁰, NR10COR¹⁰, NR¹⁰CO₂R¹⁰,NR¹⁰CONR¹², CR¹⁰R¹¹CO₂R¹⁰ or CR¹⁰R¹¹0COR¹⁰; R², R³, R⁴, R⁵ and R⁶ areeach, independently, H, OH, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, C₁₋₆ thioalkoxy, NR¹⁰R¹², NR¹⁰CO₂R¹¹, NR¹⁰CONR¹⁰R¹²,NR¹⁰SO₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, heterocyclyl, carbocyclyl, carbocyclyloxy,heterocyclyloxy, CN, NO₂, COR¹¹, CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR^(1O),SOR^(1O)SO₂R¹⁰; or SO₂—NR¹⁰R¹²; R⁷ is H or C₁₋₈ alkyl optionallysubstituted by 1, 2, 3, 4, 5 or 6 substituents independently selectedfrom halo, C₁₋₁₀ haloalkyl, Cy, CN, NO₂, OR^(a), C(O)R^(b),C(O)NR^(C)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(C)R^(d), NR^(c)R^(d),NR^(C)C(O)R^(b), NR^(C)C(O)NR^(C)R^(d), NR^(C)C(O)OR^(a), S(O)R^(b),S(O)NR^(C)R^(d), S(O)₂R^(b), NR^(C)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); orR⁷ is H, C₁₋₈alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, —O—C₁₋₆alkyl, —NR^(12a)R^(12a),—NR^(12a)COR^(13a), —NR^(12a)SO₂R^(14a), COR^(11a), —CONR^(12a)R^(12a),phenyl and heterocycle, where the alkyl, phenyl, and heterocycle areunsubstituted or substituted with 1-3 substituents selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, trifluoromethyl,and —SO₂C₁₋₆alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, halo, —O—C₁₋₆ alkyl, CN,—NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a), —COR^(11a),—CONR^(12a)R^(12a), phenyl and heterocycle, where the alkyl, phenyl, andheterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy, —C0₂H,—C0₂—C₁₋₆alkyl, and trifluoromethyl; or R⁷ is H, C₁₋₆alkyl unsubstitutedor substituted with 1-3 substituents selected from: halo, hydroxy,—C0₂H, —C0₂C₁₋₆alkyl, and —O—C¹⁻³alkyl; R⁸ is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl,or heterocycloalkyl, wherein said C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from oxo, hydroxy, halo, C₁₋₄ alkyl,C₁₋₄alkoxy, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′, —(C₁₋₄ alkyl)-Cy′, CN, NO₂,—(CH₂)_(q)—ORa′, —(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)^(b′),—(CH₂)_(q)—C(O)NR^(C′)R^(d)′, —(CH₂)_(q)—C(O)OR^(a′),—(CH₂)_(q)—S(O)R^(b′), —(CH₂)_(q)—S(O)₂R^(b′), and—(CH₂)_(q)—S(O)₂NR^(c′) R^(d′); or R⁸ is selected from C₁₋₁₀alkyl,—SO₂C₁₋₁₀alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5substituents selected from: hydroxy, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,CN, —NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),—COR^(12a), S0₂R^(14a), heterocycle, ═O (where the oxygen is connectedvia a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxyand heterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —COR^(11a), —CN,—NR^(12a)R^(12a), —S0₂R^(14a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),and —CONR^(12a)R^(12a), where the alkyl and alkoxy are optionallysubstituted with 1-5 fluoro; or R⁸ is a group of formula:

Y and Z are independently selected from —O—, —NR^(12b), —S—, —SO—, SO₂—,—CR^(12b)R^(12b)—, NSO₂R^(14b)—, —NCOR^(13b)—, —CR^(12b)COR^(11b)—,—CR^(12b)OCOR^(13b)—, —C— and —CO—; R^(8a) is selected from: hydrogen,C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b), fluoro, —O—C₁₋₃alkylunsubstituted or substituted with 1-3 fluoro, C₃₋₆cycloalkyl,—O—C₃₋₆cycloalkyl, hydroxy, —COR^(11b), —OCOR^(13b); or R⁷ and R^(8a)together are C₂₋₄alkyl or C₀₋₂alkyl-O—C₁₋₃alkyl, forming a 5-7 memberedring; R^(9a) is selected from: hydrogen, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 substituents selected from fluoro, C₁₋₃alkoxy,hydroxy and —COR^(11b), COR^(11b), hydroxy and —O—C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and —COR^(11b); or R^(8a) and R^(9a) together areC₁₋₄alkyl or C₀₋₃alkyl-O—C₀₋₃alkyl, forming a 3-6 membered ring; R^(10a)is selected from: hydrogen, hydroxy, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 fluoro, fluoro, —O—C₃₋₆cycloalkyl and —O—C₁₋₃alkylunsubstituted or substituted with 1-6 fluoro; or R^(8a) and R^(ma)together are C₂₋₃alkyl, forming a 5-6 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy; orR^(8a) and R^(10a) together are O—C₁₋₂alkyl-O—C₁₋₂alkyl, forming a 6-8membered ring, where said alkyl is unsubstituted or substituted with 1-3substituents independently selected from halo, hydroxy, —COR^(11b),C₁₋₃alkyl and C₁₋₃alkoxy; or R^(8a) and R^(10a) together are—O—C₁₋₂alkyl-O—, forming a 6-7 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, —COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy;R^(11a) and R^(11b) are independently selected from: hydroxy, hydrogen,C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl, phenyl and C₃₋₆cycloalkyl, where saidalkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; R^(12a) and R^(12b) are independently selected from:hydrogen, hydroxy, C₁₋₆alkyl, benzyl, phenyl, C₃₋₆ cycloalkyl, where thealkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; or R^(12a) and R^(12b) are selected from: C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and COR^(11b), fluoro, —O—C₁₋₃alkyl unsubstituted orsubstituted with 1-6 fluoro, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, hydroxy,—O—C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b); R^(13a) and R^(13b) areindependently selected from: hydrogen, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy,—CO₂H, —CO₂—C₁₋₆alkyl, and trifluoromethyl; R^(14a) and R^(14b)independently selected from: hydroxy, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H,—CO₂—C₁₋₆alkyl, and trifluoromethyl; Cy and Cy′ are, independently,aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromoxo, hydroxy, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(C″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(C″)R^(d″), NR^(c″)R^(d″),NR^(C″)C(O)R^(b″), NR^(C″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(C″)R^(b″),and S(O)₂NR^(C″)R^(d″), aryl, or heteroaryl, cycloalkyl, orheterocycloalkyl; R⁹ is H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R¹⁰ is H, C₁₋₆alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl, wherein said C₁₋₆ alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R¹¹ is H, OH,C₁₋₆alkyl, C₁₋₆ alkoxy, benzyl, phenyl, benzyloxy, phenyloxy,C₃₋₆cycloalkyl or C₃₋₆cycloalkyloxy, wherein said C₁₋₆alkyl, C₁₋₆alkoxy,benzyl, phenyl, benzyloxy, phenyloxy, C₃₋₆cycloalkyl orC₃₋₆cycloalkyloxy, is optionally substituted with 1, 2 or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, CO₂H,CO₂—(C₁₋₆alkyl) and CF₃; R¹² is H, C¹⁻⁶alkyl, benzyl, phenyl, or C³⁻⁶cycloalkyl, wherein said C₁₋₆alkyl, benzyl, phenyl, or C₃₋₆cycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R^(a), R^(a′) and R^(a″) are,independently, H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R^(b), R^(b′) and R^(b″) are, independently, H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; R^(C) and R^(d) are, independently, H, C₁₋₁₀alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; or R^(C) and R^(d) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;R^(c)′ and R^(d′) are, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;or R^(C′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; R^(C″) and R^(d″) are,independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R^(C″) and R^(d″)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; m is 0, 1, or 2; n is 0 or 1; p is 0 or 1; and qis 0, 1, 2, or
 3. 60. The method of claim 59 wherein said chemokinereceptor is CCR2 or CCR5.
 61. The method of claim 59 wherein saidmodulating is inhibiting.
 62. A method of treating a disease associatedwith expression or activity of a chemokine receptor in a patientcomprising administering to said patient a therapeutically effectiveamount of a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier, wherein; a dashed line indicates anoptional bond; W is:

V is N, NO or CR⁵; X is N, NO or CR²; Y is N, NO or CR³; Z is N, NO orCR⁴; wherein no more than one of V, X, Y and Z is NO; L is C₁₋₄alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, C(O), C(O)NR⁹, S(O)NR⁹,S(O)₂, or S(O)₂NR⁹, R^(A), R^(A1), R^(B) and R^(B1) are each,Independently, HOH, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, heterocyclyl, carbocyclyl,NR¹⁰R¹², NR¹⁰CO₂R¹¹; NR¹⁰CONR¹⁰R¹², NR¹⁰S0₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, CN,CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR¹⁰, SOR¹⁰, SO₂R¹⁰, or SO₂—NR¹⁰R¹²; R¹ is C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₀₋₆alkyl)-O-(C1_(—)6alkyl), —(C₀₋₆alkyl)-S(C₁₋₆ alkyl), —(C₀₋₆alkyl)-(C₃₋₇ cycloalkyl)-(C₀₋₆alkyl), OH, OR¹⁰, SR¹⁰, COR¹¹, CO₂R¹⁰, CONR¹⁰R¹², carbocyclyl,heterocyclyl, CN, NR¹⁰R¹², NR¹⁰—SO₂R¹⁰, NR10COR¹⁰, NR¹⁰CO₂R¹⁰,NR¹⁰CONR¹², CR¹⁰R¹¹CO₂R¹⁰ or CR¹⁰R¹¹0COR¹⁰; R², R³, R⁴, R⁵ and R⁶ areeach, independently, H, OH, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, C₁₋₆ thioalkoxy, NR¹⁰R¹², NR¹⁰CO₂R¹¹, NR¹⁰CONR¹⁰R¹²,NR¹⁰SO₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, heterocyclyl, carbocyclyl, carbocyclyloxy,heterocyclyloxy, CN, NO₂, COR¹¹, CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR^(1O),SOR^(1O)SO₂R¹⁰; or SO₂—NR¹⁰R¹²; R⁷ is H or C₁₋₈ alkyl optionallysubstituted by 1, 2, 3, 4, 5 or 6 substituents independently selectedfrom halo, C₁₋₁₀ haloalkyl, Cy, CN, NO₂, OR^(a), C(O)R^(b),C(O)NR^(C)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(C)R^(d), NR^(c)R^(d),NR^(C)C(O)R^(b), NR^(C)C(O)NR^(C)R^(d), NR^(C)C(O)OR^(a), S(O)R^(b),S(O)NR^(C)R^(d), S(O)₂R^(b), NR^(C)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); orR⁷ is H, C₁₋₈alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, —O—C₁₋₆alkyl, —NR^(12a)R^(12a),—NR^(12a)COR^(13a), —NR^(12a)SO₂R^(14a), COR^(11a), —CONR^(12a)R^(12a),phenyl and heterocycle, where the alkyl, phenyl, and heterocycle areunsubstituted or substituted with 1-3 substituents selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, trifluoromethyl,and —SO₂C₁₋₆alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, halo, —O—C₁₋₆ alkyl, CN,—NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a), —COR^(11a),—CONR^(12a)R^(12a), phenyl and heterocycle, where the alkyl, phenyl, andheterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy, —C0₂H,—C0₂—C₁₋₆alkyl, and trifluoromethyl; or R⁷ is H, C₁₋₆alkyl unsubstitutedor substituted with 1-3 substituents selected from: halo, hydroxy,—C0₂H, —C0₂C₁₋₆alkyl, and —O—C¹⁻³alkyl; R⁸ is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl,or heterocycloalkyl, wherein said C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from oxo, hydroxy, halo, C₁₋₄ alkyl,C₁₋₄alkoxy, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′, —(C₁₋₄ alkyl)-Cy′, CN, NO₂,—(CH₂)_(q)—ORa′, —(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)^(b′),—(CH₂)_(q)—C(O)NR^(C′)R^(d)′, —(CH₂)_(q)—C(O)OR^(a′),—(CH₂)_(q)—S(O)R^(b′), —(CH₂)_(q)—S(O)₂R^(b′), and—(CH₂)_(q)—S(O)₂NR^(c′) R^(d′); or R⁸ is selected from C₁₋₁₀alkyl,—SO₂C₁₋₁₀alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5substituents selected from: hydroxy, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,CN, —NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),—COR^(12a), S0₂R^(14a), heterocycle, ═O (where the oxygen is connectedvia a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxyand heterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —COR^(11a), —CN,—NR^(12a)R^(12a), —S0₂R^(14a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),and —CONR^(12a)R^(12a), where the alkyl and alkoxy are optionallysubstituted with 1-5 fluoro; or R⁸ is a group of formula:

Y and Z are independently selected from —O—, —NR^(12b), —S—, —SO—, SO₂—,—CR^(12b)R^(12b)—, NSO₂R^(14b)—, —NCOR^(13b)—, —CR^(12b)COR^(11b)—,—CR^(12b)OCOR^(13b)—, —C— and —CO—; R^(8a) is selected from: hydrogen,C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b), fluoro, —O—C₁₋₃alkylunsubstituted or substituted with 1-3 fluoro, C₃₋₆cycloalkyl,—O—C₃₋₆cycloalkyl, hydroxy, —COR^(11b), —OCOR^(13b); or R⁷ and R^(8a)together are C₂₋₄alkyl or C₀₋₂alkyl-O—C₁₋₃alkyl, forming a 5-7 memberedring; R^(9a) is selected from: hydrogen, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 substituents selected from fluoro, C₁₋₃alkoxy,hydroxy and —COR^(11b), COR^(11b), hydroxy and —O—C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and —COR^(11b); or R^(8a) and R^(9a) together areC₁₋₄alkyl or C₀₋₃alkyl-O—C₀₋₃alkyl, forming a 3-6 membered ring; R^(10a)is selected from: hydrogen, hydroxy, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 fluoro, fluoro, —O—C₃₋₆cycloalkyl and —O—C₁₋₃alkylunsubstituted or substituted with 1-6 fluoro; or R^(8a) and R^(ma)together are C₂₋₃alkyl, forming a 5-6 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy; orR^(8a) and R^(10a) together are O—C₁₋₂alkyl-O—C₁₋₂alkyl, forming a 6-8membered ring, where said alkyl is unsubstituted or substituted with 1-3substituents independently selected from halo, hydroxy, —COR^(11b),C₁₋₃alkyl and C₁₋₃alkoxy; or R^(8a) and R^(10a) together are—O—C₁₋₂alkyl-O—, forming a 6-7 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, —COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy;R^(11a) and R^(11b) are independently selected from: hydroxy, hydrogen,C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl, phenyl and C₃₋₆cycloalkyl, where saidalkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; R^(12a) and R^(12b) are independently selected from:hydrogen, hydroxy, C₁₋₆alkyl, benzyl, phenyl, C₃₋₆ cycloalkyl, where thealkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; or R^(12a) and R^(12b) are selected from: C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and COR^(11b), fluoro, —O—C₁₋₃alkyl unsubstituted orsubstituted with 1-6 fluoro, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, hydroxy,—O—C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b); R^(13a) and R^(13b) areindependently selected from: hydrogen, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy,—CO₂H, —CO₂—C₁₋₆alkyl, and trifluoromethyl; R^(14a) and R^(14b)independently selected from: hydroxy, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H,—CO₂—C₁₋₆alkyl, and trifluoromethyl; Cy and Cy′ are, independently,aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromoxo, hydroxy, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(C″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(C″)R^(d″), NR^(c″)R^(d″),NR^(C″)C(O)R^(b″), NR^(C″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(C″)R^(b″),and S(O)₂NR^(C″)R^(d″), aryl, or heteroaryl, cycloalkyl, orheterocycloalkyl; R⁹ is H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R¹⁰ is H, C₁₋₆alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl, wherein said C₁₋₆ alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R¹¹ is H, OH,C₁₋₆alkyl, C₁₋₆ alkoxy, benzyl, phenyl, benzyloxy, phenyloxy,C₃₋₆cycloalkyl or C₃₋₆cycloalkyloxy, wherein said C₁₋₆alkyl, C₁₋₆alkoxy,benzyl, phenyl, benzyloxy, phenyloxy, C₃₋₆cycloalkyl orC₃₋₆cycloalkyloxy, is optionally substituted with 1, 2 or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, CO₂H,CO₂—(C₁₋₆alkyl) and CF₃; R¹² is H, C¹⁻⁶alkyl, benzyl, phenyl, or C³⁻⁶cycloalkyl, wherein said C₁₋₆alkyl, benzyl, phenyl, or C₃₋₆cycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R^(a), R^(a′) and R^(a″) are,independently, H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R^(b), R^(b′) and R^(b″) are, independently, H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; R^(C) and R^(d) are, independently, H, C₁₋₁₀alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; or R^(C) and R^(d) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;R^(c)′ and R^(d′) are, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;or R^(C′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; R^(C″) and R^(d″) are,independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R^(C″) and R^(d″)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; m is 0, 1, or 2; n is 0 or 1; p is 0 or 1; and qis 0, 1, 2, or
 3. 63. The method of claim 62 wherein said chemokinereceptor is CCR2 or CCR5.
 64. The method of claim 62 wherein saiddisease is an inflammatory disease.
 65. The method of claim 64 furthercomprising administering an anti-inflammatory agent.
 66. The method ofclaim 65 wherein said anti-inflammatory agent is an antibody.
 67. Themethod of claim 62 wherein said disease is an immune disorder.
 68. Themethod of claim 62 wherein said disease is rheumatoid arthritis,atherosclerosis, lupus, multiple sclerosis, pain, neuropathic pain,transplant rejection, diabetes, or obesity.
 69. The method of claim 62wherein said disease is cancer.
 70. The method of claim 69 wherein saidcancer is characterized by tumor associated macrophages.
 71. The methodof claim 69 wherein said cancer is breast cancer, ovarian cancer ormultiple myeloma.
 72. The method of claim 62 wherein said disease orcondition is a viral infection.
 73. The method of claim 72 wherein saidviral infection is HIV infection.
 74. A method of treating HIV infectionin a patient comprising administering to said patient a therapeuticallyeffective amount of a compound of Formula I:

or a pharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier, wherein; a dashed line indicates anoptional bond; W is:

V is N, NO or CR⁵; X is N, NO or CR²; Y is N, NO or CR³; Z is N, NO orCR⁴; wherein no more than one of V, X, Y and Z is NO; L is C₁₋₄alkylenyl, C₂₋₄ alkenylenyl, C₂₋₄ alkynylenyl, C(O), C(O)NR⁹, S(O)NR⁹,S(O)₂, or S(O)₂NR⁹, R^(A), R^(A1), R^(B) and R^(B1) are each,Independently, HOH, halo, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆alkoxy, C₁₋₆haloalkoxy, heterocyclyl, carbocyclyl,NR¹⁰R¹², NR¹⁰CO₂R¹¹; NR¹⁰CONR¹⁰R¹², NR¹⁰S0₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, CN,CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR¹⁰, SOR¹⁰, SO₂R¹⁰, or SO₂—NR¹⁰R¹²; R¹ is C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, —(C₀₋₆alkyl)-O-(C1_(—)6alkyl), —(C₀₋₆alkyl)-S(C₁₋₆ alkyl), —(C₀₋₆alkyl)-(C₃₋₇ cycloalkyl)-(C₀₋₆alkyl), OH, OR¹⁰, SR¹⁰, COR¹¹, CO₂R¹⁰, CONR¹⁰R¹², carbocyclyl,heterocyclyl, CN, NR¹⁰R¹², NR¹⁰—SO₂R¹⁰, NR10COR¹⁰, NR¹⁰CO₂R¹⁰,NR¹⁰CONR¹², CR¹⁰R¹¹CO₂R¹⁰ or CR¹⁰R¹¹0COR¹⁰; R², R³, R⁴, R⁵ and R⁶ areeach, independently, H, OH, halo, C₁₋₆alkyl, C₁₋₆haloalkyl, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, C₁₋₆ thioalkoxy, NR¹⁰R¹², NR¹⁰CO₂R¹¹, NR¹⁰CONR¹⁰R¹²,NR¹⁰SO₂NR¹⁰R¹², NR¹⁰—SO₂—R¹¹, heterocyclyl, carbocyclyl, carbocyclyloxy,heterocyclyloxy, CN, NO₂, COR¹¹, CONR¹⁰R¹², CO₂R¹⁰, NO₂, SR^(1O),SOR^(1O)SO₂R¹⁰; or SO₂—NR¹⁰R¹²; R⁷ is H or C₁₋₈ alkyl optionallysubstituted by 1, 2, 3, 4, 5 or 6 substituents independently selectedfrom halo, C₁₋₁₀ haloalkyl, Cy, CN, NO₂, OR^(a), C(O)R^(b),C(O)NR^(C)R^(d), C(O)OR^(a), OC(O)R^(b), OC(O)NR^(C)R^(d), NR^(c)R^(d),NR^(C)C(O)R^(b), NR^(C)C(O)NR^(C)R^(d), NR^(C)C(O)OR^(a), S(O)R^(b),S(O)NR^(C)R^(d), S(O)₂R^(b), NR^(C)S(O)₂R^(b), and S(O)₂NR^(c)R^(d); orR⁷ is H, C₁₋₈alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, —O—C₁₋₆alkyl, —NR^(12a)R^(12a),—NR^(12a)COR^(13a), —NR^(12a)SO₂R^(14a), COR^(11a), —CONR^(12a)R^(12a),phenyl and heterocycle, where the alkyl, phenyl, and heterocycle areunsubstituted or substituted with 1-3 substituents selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, trifluoromethyl,and —SO₂C₁₋₆alkyl which is unsubstituted or substituted with 1-6substituents selected from: hydroxy, halo, —O—C₁₋₆ alkyl, CN,—NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a), —COR^(11a),—CONR^(12a)R^(12a), phenyl and heterocycle, where the alkyl, phenyl, andheterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃ alkyl, C₁₋₃alkoxy, —C0₂H,—C0₂—C₁₋₆alkyl, and trifluoromethyl; or R⁷ is H, C₁₋₆alkyl unsubstitutedor substituted with 1-3 substituents selected from: halo, hydroxy,—C0₂H, —C0₂C₁₋₆alkyl, and —O—C¹⁻³alkyl; R⁸ is C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl,or heterocycloalkyl, wherein said C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, C₁₋₁₀ haloalkyl, aryl, cycloalkyl, heteroaryl, orheterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, or 6substituents independently selected from oxo, hydroxy, halo, C₁₋₄ alkyl,C₁₋₄alkoxy, C₂₋₄ alkenyl, C₂₋₄alkynyl, C₁₋₄ haloalkyl, C₁₋₄hydroxyalkyl, C₁₋₄ cyanoalkyl, Cy′, —(C₁₋₄ alkyl)-Cy′, CN, NO₂,—(CH₂)_(q)—ORa′, —(CH₂)_(q)—SR^(a′), —(CH₂)_(q)—C(O)^(b′),—(CH₂)_(q)—C(O)NR^(C′)R^(d)′, —(CH₂)_(q)—C(O)OR^(a′),—(CH₂)_(q)—S(O)R^(b′), —(CH₂)_(q)—S(O)₂R^(b′), and—(CH₂)_(q)—S(O)₂NR^(c′) R^(d′); or R⁸ is selected from C₁₋₁₀alkyl,—SO₂C₁₋₁₀alkyl, pyridyl or phenyl, unsubstituted or substituted with 1-5substituents selected from: hydroxy, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,CN, —NR^(12a)R^(12a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),—COR^(12a), S0₂R^(14a), heterocycle, ═O (where the oxygen is connectedvia a double bond), phenoxy and phenyl, where the alkyl, phenyl, phenoxyand heterocycle are unsubstituted or substituted with 1-3 substituentsselected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —COR^(11a), —CN,—NR^(12a)R^(12a), —S0₂R^(14a), —NR^(12a)COR^(13a), —NR^(12a)S0₂R^(14a),and —CONR^(12a)R^(12a), where the alkyl and alkoxy are optionallysubstituted with 1-5 fluoro; or R⁸ is a group of formula:

Y and Z are independently selected from —O—, —NR^(12b), —S—, —SO—, SO₂—,—CR^(12b)R^(12b)—, NSO₂R^(14b)—, —NCOR^(13b)—, —CR^(12b)COR^(11b)—,—CR^(12b)OCOR^(13b)—, —C— and —CO—; R^(8a) is selected from: hydrogen,C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b), fluoro, —O—C₁₋₃alkylunsubstituted or substituted with 1-3 fluoro, C₃₋₆cycloalkyl,—O—C₃₋₆cycloalkyl, hydroxy, —COR^(11b), —OCOR^(13b); or R⁷ and R^(8a)together are C₂₋₄alkyl or C₀₋₂alkyl-O—C₁₋₃alkyl, forming a 5-7 memberedring; R^(9a) is selected from: hydrogen, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 substituents selected from fluoro, C₁₋₃alkoxy,hydroxy and —COR^(11b), COR^(11b), hydroxy and —O—C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and —COR^(11b); or R^(8a) and R^(9a) together areC₁₋₄alkyl or C₀₋₃alkyl-O—C₀₋₃alkyl, forming a 3-6 membered ring; R^(10a)is selected from: hydrogen, hydroxy, C₁₋₆alkyl unsubstituted orsubstituted with 1-6 fluoro, fluoro, —O—C₃₋₆cycloalkyl and —O—C₁₋₃alkylunsubstituted or substituted with 1-6 fluoro; or R^(8a) and R^(ma)together are C₂₋₃alkyl, forming a 5-6 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy; orR^(8a) and R^(10a) together are O—C₁₋₂alkyl-O—C₁₋₂alkyl, forming a 6-8membered ring, where said alkyl is unsubstituted or substituted with 1-3substituents independently selected from halo, hydroxy, —COR^(11b),C₁₋₃alkyl and C₁₋₃alkoxy; or R^(8a) and R^(10a) together are—O—C₁₋₂alkyl-O—, forming a 6-7 membered ring, where said alkyl isunsubstituted or substituted with 1-3 substituents independentlyselected from halo, hydroxy, —COR^(11b), C₁₋₃alkyl and C₁₋₃alkoxy;R^(11a) and R^(11b) are independently selected from: hydroxy, hydrogen,C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl, phenyl and C₃₋₆cycloalkyl, where saidalkyl, phenyl, benzyl and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, —CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; R^(12a) and R^(12b) are independently selected from:hydrogen, hydroxy, C₁₋₆alkyl, benzyl, phenyl, C₃₋₆ cycloalkyl, where thealkyl, phenyl, benzyl, and cycloalkyl groups are unsubstituted orsubstituted with 1-3 substituents independently selected from: halo,hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H, —CO₂—C₁₋₆alkyl, andtrifluoromethyl; or R^(12a) and R^(12b) are selected from: C₁₋₆alkylunsubstituted or substituted with 1-6 substituents selected from fluoro,C₁₋₃alkoxy, hydroxy and COR^(11b), fluoro, —O—C₁₋₃alkyl unsubstituted orsubstituted with 1-6 fluoro, C₃₋₆cycloalkyl, —O—C₃₋₆cycloalkyl, hydroxy,—O—C₁₋₆alkyl unsubstituted or substituted with 1-6 substituents selectedfrom fluoro, C₁₋₃alkoxy, hydroxy and —COR^(11b); R^(13a) and R^(13b) areindependently selected from: hydrogen, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy,—CO₂H, —CO₂—C₁₋₆alkyl, and trifluoromethyl; R^(14a) and R^(14b)independently selected from: hydroxy, C₁₋₆alkyl, —O—C₁₋₆alkyl, benzyl,phenyl, C₃₋₆ cycloalkyl, where the alkyl, phenyl, benzyl, and cycloalkylgroups are unsubstituted or substituted with 1-3 substituentsindependently selected from: halo, hydroxy, C₁₋₃alkyl, C₁₋₃alkoxy, CO₂H,—CO₂—C₁₋₆alkyl, and trifluoromethyl; Cy and Cy′ are, independently,aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, each optionallysubstituted by 1, 2, 3, 4 or 5 substituents independently selected fromoxo, hydroxy, halo, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₁₋₄haloalkyl, CN, NO₂, OR^(a″), SR^(a″), C(O)R^(b″), C(O)NR^(C″)R^(d″),C(O)OR^(a″), OC(O)R^(b″), OC(O)NR^(C″)R^(d″), NR^(c″)R^(d″),NR^(C″)C(O)R^(b″), NR^(C″)C(O)OR^(a″), S(O)R^(b″), S(O)NR^(C″)R^(b″),and S(O)₂NR^(C″)R^(d″), aryl, or heteroaryl, cycloalkyl, orheterocycloalkyl; R⁹ is H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆haloalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R¹⁰ is H, C₁₋₆alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl, wherein said C₁₋₆ alkyl, benzyl, phenyl, orC₃₋₆cycloalkyl is optionally substituted with 1, 2, or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃alkoxy, C₁₋₃ haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R¹¹ is H, OH,C₁₋₆alkyl, C₁₋₆ alkoxy, benzyl, phenyl, benzyloxy, phenyloxy,C₃₋₆cycloalkyl or C₃₋₆cycloalkyloxy, wherein said C₁₋₆alkyl, C₁₋₆alkoxy,benzyl, phenyl, benzyloxy, phenyloxy, C₃₋₆cycloalkyl orC₃₋₆cycloalkyloxy, is optionally substituted with 1, 2 or 3 substituentsindependently selected from halo, OH, C₁₋₃ alkyl, C₁₋₃ alkoxy, CO₂H,CO₂—(C₁₋₆alkyl) and CF₃; R¹² is H, C¹⁻⁶alkyl, benzyl, phenyl, or C³⁻⁶cycloalkyl, wherein said C₁₋₆alkyl, benzyl, phenyl, or C₃₋₆cycloalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from halo, OH, C₁₋₃ alkyl, C₁₋₃ haloalkyl, C₁₋₃ alkoxy, C₁₋₃haloalkoxy, CO₂H, and CO₂—(C₁₋₆alkyl); R^(a), R^(a′) and R^(a″) are,independently, H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,C₂₋₆alkynyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl,heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl andheterocycloalkyl; R^(b), R^(b′) and R^(b″) are, independently, H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; R^(C) and R^(d) are, independently, H, C₁₋₁₀alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl,heteroaryl, cycloalkyl, heterocyclo alkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl is optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆alkyl,C₁₋₆haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; or R^(C) and R^(d) together with the N atom towhich they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkylgroup optionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;R^(c)′ and R^(d′) are, independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl orheterocycloalkylalkyl, wherein said C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl isoptionally substituted with 1, 2, or 3 substituents independentlyselected from OH, amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl and heterocycloalkyl;or R^(C′) and R^(d′) together with the N atom to which they are attachedform a 4-, 5-, 6- or 7-membered heterocycloalkyl group optionallysubstituted with 1, 2, or 3 substituents independently selected from OH,amino, halo, C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; R^(C″) and R^(d″) are,independently, H, C₁₋₁₀ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl,heteroarylalkyl, cycloalkylalkyl or heterocycloalkylalkyl, wherein saidC₁₋₁₀ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, aryl,heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,cycloalkylalkyl or heterocycloalkylalkyl is optionally substituted with1, 2, or 3 substituents independently selected from OH, amino, halo,C₁₋₆ alkyl, C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, cycloalkyl and heterocycloalkyl; or R^(C″) and R^(d″)together with the N atom to which they are attached form a 4-, 5-, 6- or7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3substituents independently selected from OH, amino, halo, C₁₋₆ alkyl,C₁₋₆ haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyland heterocycloalkyl; m is 0, 1, or 2; n is 0 or 1; p is 0 or 1; and qis 0, 1, 2, or
 3. 75. The method of claim 74 further comprisingsimultaneously or sequentially administering at least one anti-viralagent.